domain: shs info

text:
Anuragini Shirish

Leslie Batuekueno

Technology Renewal, User Resistance, User Adoption: Status Quo Bias Theory Revisited

Keywords: Technology Renewal, User Resistance, User Adoption: Status Quo Bias Theory Revisited Technology renewal, digital transformation projects, human resource systems, IT department employees, status quo bias, user resistance, technology adoption, IT use, change management, France

Methodology:

We used survey method to gather data. All items were based on prior literature.

We administrated the survey to employees of GOODTECH (name changed), information systems department members, situated in France. We obtained 103 valid responses along with usage data from the system to run our path model in order to validate our proposed research model.

Purpose:

The article provides a conceptual replication and enrichment of the status quo bias theory in the specific context of understanding IT department user resistance and user adoption.

The findings can assist technology renewals and associated change management professionals to assess and plan the adoption and active usage of human resource systems.

Findings:

The study offers an enriched user resistance model to understand why IT savvy employees would resist or adopt new human resource tools. Apart from providing partial validity to status quo bias theory in the French context, the enriched model uses behavioral intention to use as an intermediate variable to explain the influence of two key construct of the original theory: Switching cost and Switching benefits. This research provides a better explanatory power to understand the cause of user resistance and new IT use.

Limitations:

The sample size used in the study can be considered as a limitation, although power analysis reveals that the results are significant and valid. The context of the study is also limited to one country and to a specific type of information systems implementation scenario.

Since the purpose of the paper was to offer contextual theory enhancement, therefore the findings are valid for this purpose. Practical Implications: Digital project managers are offered a framework to increase technology adoption of new human resource tools and evaluate how to reduce user resistance at times of technology renewals. Self-efficacy for change and colleagues opinion can indirectly impact behavioral intention to use via switching cost and switching benefit perceptions and thus reduce resistance perceptions as well as increase adoption of new IT tools in post implementation phases. Originality: The paper enriches the well-established user resistance theory (URM) in information systems domain in a context of human resource post implementation phase by studying IT savvy end user's perception. The paper demonstrates the need to integrate user adoption and user resistance variables in one parsimonious framework and extends support to emerging research in this area.

Introduction

With the growing need of digitalization, information systems (IS) implementation projects are ever increasing. The implementation of a new IS, often undertaken as a technology renewal comes with the notion of change and management of tensions within organizations [START_REF] Wimelius | A paradoxical perspective on technology renewal in digital transformation[END_REF]. Organizations invest in information technology to gain productivity and innovation gains [START_REF] Chandra | Theorizing technological spatial intrusion for ICT enabled employee innovation: the mediating role of perceived usefulness[END_REF], nevertheless, these benefits are reliant on the successful implementation of new IT tools and their adoption by stakeholders. Human reaction to change puts resistance to change as a core and unavoidable concept to any change initiative [START_REF] Lee | Examining the use of status quo bias perspective in IS research: need for re-conceptualizing and incorporating biases[END_REF][START_REF] Visinand | Le rôle attendu des professionnels RH lors d'un changement organisationnel[END_REF][START_REF] Irani | The propagation of technology management taxonomies for evaluating investments in information systems[END_REF]. Human resource is one of the least equipped and most promising function that can benefit from technology renewals and change management initiatives with companywide impact (Forbes, 2020). Thus, it is important to focus both on the IT resistance and IT usage when examining the implementation of a new HR tool as part of a digital transformation project in its unique context to advance theory and practice [START_REF] Dennis | Editor's Comments: Replication Crisis or Replication Reassurance: Results of the IS Replication Project[END_REF].

Adoption and resistance are twin concepts that go hand in hand with any digital transformation or change management initiatives. User resistance has been defined by [START_REF] Collerette | Le changement organisationnel: théorie et pratique[END_REF] as an implicit or explicit defense's expression towards a change. Thus, resistance to change is a seen as something that organizations should strive to remove [START_REF] Kossek | Waiting for innovation in the human resources department: Godot implements a human resource information system[END_REF]. Some other scholars also see it as a way to identify user level frustrations linked to a flawed information system management [START_REF] Marakas | Passive resistance misuse: overt support and covert recalcitrance in IS implementation[END_REF].

Previous research on user resistance has mainly explained the cause of resistance to change amongst end users who are not particularly tech savvy employees. First stream of research speaks about the role of the user and their knowledge loss perceptions as the primary cause of the resistance [START_REF] Bareil | La résistance au changement: synthèse et critique des écrits[END_REF][START_REF] Dent | Challenging "resistance to change[END_REF]. The second finds its roots in the quality of the implementation and thus puts the onus on the organizations undertaking the IT implementation and the change to be the cause of resistance and adoption issues. Third stream explains that the expectation of repeated change itself causes resistance, which then translates to the failure of the implementation of change programs in organizations [START_REF] Abrahamson | Avoiding repetitive change syndrome[END_REF].

More specifically, within the information systems (IS) domain, several scholars have studied IT user resistance in particular [START_REF] Lapointe | A multilevel model of resistance to information technology implementation[END_REF][START_REF] Markus | Power, politics, and MIS implementation[END_REF] but they call for more context oriented implementation examination [START_REF] Dwivedi | Research on information systems failures and successes: Status update and future directions[END_REF]. Appendix 1 provides a table summarizing the key research in IT use and resistance. Out of the various theoretical perspectives, one of the most holistic framework to investigate the phenomenon of user resistance in an applied setting is the status quo bias perspective [START_REF] Kim | Investigating user resistance to information systems implementation: A status quo bias perspective[END_REF]. Status quo bias theory (URM) aims to explain people's preference for maintaining their IT use current status and accounts for the loss and the threat perceptions experienced by an end user of an IT tool [START_REF] Kim | Investigating user resistance to information systems implementation: A status quo bias perspective[END_REF]. This theory is particularly amenable to studying both user adoption and user resistance as it offers an integrative model for adoption of IT tools for further investigation. However, past studies have not attempted to enrich this model by incorporating IT adoption concepts. Dual focus of IT use and IT resistance research stream is a new emerging field that requires further investigation [START_REF] Beaudry | Impact of IT User Behavior: Observations through a New Lens[END_REF].

It may not appear to be ill logical to assume that employees working in IT departments of organizations send a signal through their express choice of career path that they are competent in information systems management and indeed have affective connection to using new IT tools [START_REF] Paré | How Good Is the Professional's Aptitude in the Conceptual Understanding of Change Management[END_REF]. They are often considered as frontline change agents and many digital transformation projects depend on their early adoption to new IT tools to gauge their change management effectiveness. IT employees are prone to be more open to experimentation with new ITs due to their opportunity technology framing [START_REF] Shirish | Cognitive-affective appraisal of technostressors by ICT-based mobile workers and their impacts on technostrain[END_REF].

New IT tools introduction in the organization should ideally trigger such employees of the IT department to cope better with the change due to their general positive affect towards IT use [START_REF] Shirish | Cognitive-affective appraisal of technostressors by ICT-based mobile workers and their impacts on technostrain[END_REF]. Recent research also calls for treating IT professionals as new stakeholders when investigating IS success and failure phenomenon [START_REF] Kim | Do we fully understand information systems failure? An exploratory study of the cognitive schema of IS professionals[END_REF].

However, thus far, researchers have not investigated user resistance perceptions amongst IT professionals from a status quo bias perspective. Status quo bias theory is a cognitive theory that explains resistance and adoption decisions as an evaluative judgement of the end user [START_REF] Lee | Examining the use of status quo bias perspective in IS research: need for re-conceptualizing and incorporating biases[END_REF]. The relative value perception from changing their system use from an incumbent to a new system is shown to be linked to resistance perceptions. However, we know that absence of resistance does not preclude the presence of use [START_REF] Polites | Shackled to the status quo: The inhibiting effects of incumbent system habit, switching costs, and inertia on new system acceptance[END_REF] thus studying the behavioral intention to use the new technology is taken in this study as the linking variable to explicate this evaluative judgement of end users when they try to manage demands of technology renewals. However, URM theory originated in the North American context. It is important to extend the generalizability of the theory to European context specifically amongst IT professionals to offer contextual clarity and enrich the literature in this domain [START_REF] Dennis | Editor's Comments: Replication Crisis or Replication Reassurance: Results of the IS Replication Project[END_REF][START_REF] Johns | The essential impact of context on organizational behavior[END_REF]. In order to address these research gaps and offer a contextual enrichment that can provide managerial implication to change management initiatives in organizations, we seek to address the below research question in this study:

R1: In the specific context of a technological renewal initiative within a French company, what are the factors that contribute to IT user resistance and IT usage amongst IT professionals?

This study aims to extent previous research that explores the reasons for user resistance to the specific population of IT savvy end users who are often preferred as change agents in digital transformation projects. Their evaluation of change related to new information system and decision to resist it or adopt it is an important void unexplored in literature. In particular, the phenomenon of status quo bias amongst IT savvy employees and its influence on their IT adoption or resistance as a dual phenomenon is under examined despite their crucial role in technology renewal and IT project success initiatives. This study leverages the status quo bias theory and adoption literature to conceptually replicate and enrich the theory in the context of a post implementation of human resource (HR) information systems in a European context. To undertake the study, we gathered data from a French company via survey and objective data of system usage. Our results support the proposed enriched user resistance model empirically.

Behavioral intention to use the new HR tool investigated in the study was found to be an intermediate variable that explained user resistance and IT use. The results of the study offer both theoretical and practical implications to manage resistance and change amongst IT savvy employees more specifically.

We provide the investigative context and theoretical background in the following two sections of the paper. Followed by the hypothesis development section. Subsequently, we elaborate separately on the method, results and implications of the study

Investigative Context and IT Tool

The objective of this study is to empirically test user resistance model (URM) to concomitantly explicate IT user resistance and IT usage amongst IT savvy employees. The study will allow us to understand the factors leading to user adoption and user resistance in the specific context of a human resource (HR) IT tool implementation in a large French multinational corporation (MNC) called GOODTECH (pseudonym) with its headquarters in Paris. The authors designed the study to understand why the uptake of a new HR tool was not satisfactory in GOODTECH. The new HR IT tool that was introduced within its broad digital transformation project agenda involved streamlining work practices by introducing technology renewals in HR project reporting. The digital transformation project involved progressive change introduction. Users of the IT department of the MNC were chosen to be the first support unit of the company that is required to switch to the new HR tool and it is expected that the transformation would then extend to other primary and support functions incrementally within the GOOGTECH.

My Kaalsheet (name changed), is an internal tool developed by the HR IT department of GOOD TECH. It is a time entry tool that allows user to self-enter their timesheets, extra hours and absences. It was developed in parallel to two other tools that exist within the company and that allows to do the same actions: the Java Portal and Quick Time. Since there were three tools with the same usage context, the company decided to allow the HR IT department to decommission the two others, knowing that My Kaalsheet is the more efficient out of the three of them. Despite this preferred transition, only 30% of the employees were using the tools since it was released in 2017.

Enriched User Resistance Model: Theoretical Framework

Appendix 1 of the paper provides a detailed overview of various key papers discussing IT resistance and use in general. In this section, we elaborate on the specific theoretical lens used for this study. The status quo bias theory [START_REF] Samuelson | Status quo bias in decision making[END_REF], the theory of planned behavior [START_REF] Ajzen | The theory of planned behavior[END_REF] and the equity implementation model [START_REF] Joshi | A model of users' perspective on change: the case of information systems technology implementation[END_REF] were integrated to come up with a holistic theory called user resistance model [START_REF] Kim | Investigating user resistance to information systems implementation: A status quo bias perspective[END_REF]. This theory explains the physiological factors for user resistance of a new IT tools. This theory is called the user resistance model (URM) and it takes into account how human behavior (IT user resistance) can be guided by various beliefs that the user may hold. The development of this theory needed integration of behavioral, normative and control beliefs. Behavioral beliefs are about the potential outcome to IT user resistance as may be perceived by the end user. Normative beliefs are about the other oriented expectations and the motivation to comply with such expectations. Control beliefs are those that take into account the perceptions of factors that facilitate or impede the performance of IT user resistance and their respective power perceptions on the particular behavior. Although this theory explains user resistance to IT, the authors of the study also mention that it can be used to study adoption behavior [START_REF] Kim | Investigating user resistance to information systems implementation: A status quo bias perspective[END_REF]. However, prior research has so far not integrated user adoption variable into the model that is a crucial gap we plan to address in this paper.

URM theory explains user resistance through the key variables of switching cost, switching benefits, which then influence their attitude measured as 'perceived value'.

Perceived value is then shown to reduce or increase user resistance behaviors to a new IT tool.

However, this seminal work was set in the context of pre-implementation of an IT tool. The study was conducted within a major IT service company that was deploying a new enterprise portal and knowledge management system. This tool studied was not a human resource management tool that we study in this paper rather it was a tool for enterprise-wide collaboration and knowledge management functions [START_REF] Kim | Investigating user resistance to information systems implementation: A status quo bias perspective[END_REF]. Data was gathered via a survey from general employees from various functional units of the company as opposed to IT savvy employees as we do in this paper.

The study could not prove all the laid out hypothesis empirically, see Figure 1 of model proposed by [START_REF] Kim | Investigating user resistance to information systems implementation: A status quo bias perspective[END_REF]. The study posited that self-efficacy for change, organizational support for change can both directly impact user resistance and indirectly impact user resistance via switching costs perceptions. The study also posited that colleague's opinion can have a direct impact on user resistance as well as impact both switching cost and switching benefits perceptions. However, the empirical setting used in that study allowed the authors to only confirm certain hypotheses (see Figure 1).

Over the past years, the status quo bias perspective has been used in various studies starting from the exploration of the adoption of new technology implementation as cloud system [START_REF] Fan | The effect of status quo bias on cloud system adoption[END_REF] to exploring the use of an online health service [START_REF] Xiaofei | Effects of Emotional Attachment on Mobile Health-Monitoring Service Usage: An Affect Transfer Perspective[END_REF]. However, among these studies there is a lack of representation of the status quo bias perspective on IT department employees in a French context. There is little research focusing on analyzing IT user resistance and IT adoption among IT professionals more generally. There has been prior studies on resistance amongst implementers of IT tool by IT professionals [START_REF] Lapointe | A multilevel model of resistance to information technology implementation[END_REF], but IT department employee in the context of this study are not viewed as implementers in our study context they are mere users. Therefore there is need to revisit their user resistance perspective in the given context.

A brief definition of the various variables used in the enriched URM model are provided in the table below. For the purpose of this study, we are also interested in studying behavior intention to use the new IT tool. We defined it "as the degree to which a person has formulated conscious plans to adopt the new IT tool or not adopt the new IT tool in the future"(Warshaw & [START_REF] Visinand | Le rôle attendu des professionnels RH lors d'un changement organisationnel[END_REF] (p. 214).

Concepts Definitions Source Switching cost

The perceived disutility a user would incur in switching from the status quo to the new IS [START_REF] Kim | Investigating user resistance to information systems implementation: A status quo bias perspective[END_REF] Switching benefit

The perceived utility a user would enjoy in switching from the status quo to the new IS [START_REF] Kim | Investigating user resistance to information systems implementation: A status quo bias perspective[END_REF] Self-efficacy for change The internal means an individual deploys to gain control over a changing situation [START_REF] Ajzen | The theory of planned behavior[END_REF][START_REF] Ajzen | Perceived Behavioral Control, Self-Efficacy, Locus of Control, and the Theory of Planned Behavior[END_REF] Organizational support The perceived facilitation provided by the organization to make users' adaptation to new IS-related change easier. [START_REF] Kim | Investigating user resistance to information systems implementation: A status quo bias perspective[END_REF] Colleague opinion

The perception that colleagues favor the changes related to a new IS implementation. Due [START_REF] Kim | Investigating user resistance to information systems implementation: A status quo bias perspective[END_REF] Table 1: Definitions of key concepts in URM model

Although URM provides an integrative framework, the results may vary when a different set of IT tools are studied and when the context of the study may be different.

Therefore, a conceptual replication may be necessary [START_REF] Dennis | Editor's Comments: Replication Crisis or Replication Reassurance: Results of the IS Replication Project[END_REF]. A recent research that called for such work using URM dealt with the context of specific health IT tool [START_REF] Samhan | Switching to Electronic Health Record Systems: A Replication of the User Resistance Model[END_REF]. Therefore, we believe that it is theoretically and practically important and novel to re-examine and expand the URM model in the specific context of IT savvy employees who may be working within various IT departments in a distributed manner but under one large enterprise.

Further, we posit that since we use URM theory in a post implementation of HR IT tool scenario, it becomes important to measure the phenomenon that is beyond the current attitude measure of "perceived value" to see if switching costs and switching benefit can also impact "behavioral intention to use" the new HR tool [START_REF] Polites | Shackled to the status quo: The inhibiting effects of incumbent system habit, switching costs, and inertia on new system acceptance[END_REF]. This indirect relationship is perhaps more accurate than measuring its precursor. We therefore enrich the URM model by introducing behavioral intention to use as an intermediate variable between independent variables of switching cost and switching benefit on both user resistance and user adoption of the new HR tool amongst IT savvy employees.

Absence of resistance does not mean presence of usage [START_REF] Polites | Shackled to the status quo: The inhibiting effects of incumbent system habit, switching costs, and inertia on new system acceptance[END_REF].

Inertia in an IS context is defined as user attachment to, and persistence in, using an incumbent system (i.e., the status quo), even if there are better alternatives or incentives to change [START_REF] Polites | Shackled to the status quo: The inhibiting effects of incumbent system habit, switching costs, and inertia on new system acceptance[END_REF] 2) and below, we list out the new relationships argued by this study specifically.

We do not revisit in an elaborate manner the hypothesis already developed in prior study of [START_REF] Kim | Investigating user resistance to information systems implementation: A status quo bias perspective[END_REF] for brevity reasons. [START_REF] Hirschheim | Information systems and user resistance: theory and practice[END_REF]. These new conditions could influence the perceived effort expectation of users adapting to the new IT. Thus, a higher organizational support would mean reduce user resistance toward the new IT-related change as well more use of the new IT tool [START_REF] Kim | Investigating user resistance to information systems implementation: A status quo bias perspective[END_REF]. Since we wanted to focus on the novel indirect relationship in this model, we chose to focus on key antecedents to switching costs and benefits more specifically. We

Hypothesis Development

This study aims to understand the key factors that influence IT department users either to resist or to use the implementation of a new HR IT time entry tool, My Kaalsheet. These users are unique presumed to be at ease with new technologies. We posit that this IT culture may have a contextual influence on the adoption levels or the resistance levels [START_REF] Dwivedi | Research on information systems failures and successes: Status update and future directions[END_REF]. To know how does the status quo bias perception affect a population often considered as informal change champions in organization is interesting and useful.

We used the structural model (Figure 1) of the status quo bias perspective initiated by [START_REF] Kim | Investigating user resistance to information systems implementation: A status quo bias perspective[END_REF] as the basis of our research model (Figure 2). We extended the model by introducing the construct of actual IT use as another depended variable and the behavioral intention to use a mediator between switching cost and IT use/User resistance. In addition, control variables were included in the new conceptual model (Figure2). Tenure, position, age and gender, organization support for change were added as controls [START_REF] Polites | Shackled to the status quo: The inhibiting effects of incumbent system habit, switching costs, and inertia on new system acceptance[END_REF] As per the status quo bias perspective, self-efficacy for change is derived from the construct on control perceptions. Self-efficacy is defined by [START_REF] Sam | Computer self-efficacy, computer anxiety, and attitudes toward the Internet: A study among undergraduates in Unimas[END_REF] as the judgements a person makes about his or her ability to use technologies. If users have a strong self-efficacy for change, then they will be less likely to feel anxious or uncertain regarding the change [START_REF] Bandura | Self-efficacy in changing societies[END_REF][START_REF] Compeau | Social cognitive theory and individual reactions to computing technology: A longitudinal study[END_REF]. In contrast, they should feel confident with the adaption to the new IT and learning new technologies. Indeed, a high self-efficacy for change will decrease the transition cost and uncertainty cost, which lower the perception of switching cost. This self-efficacy for change perception, should be more in IT professionals.

According to [START_REF] Kim | Investigating user resistance to information systems implementation: A status quo bias perspective[END_REF], switching costs is the perceived disutility a user would incur in switching from the status quo to the new IS and is composed of three components: transition costs, uncertainty costs, and sunk costs [START_REF] Samuelson | Status quo bias in decision making[END_REF]. Transition costs are composed of the fee and permanent losses that incurred within the change situation [START_REF] Kahneman | On the interpretation of intuitive probability: A reply to Jonathan Cohen[END_REF]. The feeling of incompetence toward uncertain situation can bring anxiety and reluctance in the decision making and behavior [START_REF] Brown | Model of adoption of technology in households: A baseline model test and extension incorporating household life cycle[END_REF]. Hence, uncertainty causes negative psychological reaction [START_REF] Inder | The endowment effect and the role of uncertainty[END_REF] which leads users to rely on the status quo [START_REF] Samuelson | Status quo bias in decision making[END_REF], thus a high level of switching cost perceived in the transition cost and the uncertainty, will decrease the actual use of the tool as well increase the user resistance to the tool. Similarly, we expect a direct influence of switching cost on user resistance [START_REF] Kim | Investigating user resistance to information systems implementation: A status quo bias perspective[END_REF]. Due to reasons already stated above, the perception of uncertainty and transition cost can increase the reluctance of people toward change willing to cut the losses incurred [START_REF] Kahneman | On the interpretation of intuitive probability: A reply to Jonathan Cohen[END_REF]. The negative psychological reaction provoked by the increase of expenses and losses can lead to status quo bias [START_REF] Samuelson | Status quo bias in decision making[END_REF]. The change needed from the past investment over the investment needed in the present, is viewed as a sunk cost, leading to user resistance [START_REF] Samuelson | Status quo bias in decision making[END_REF]. Therefore, higher the switching cost will mean higher the user resistance. Thus, we posit the below: H1: Self efficacy for change will negatively impact switching cost. H2: Switching cost will negatively impact IT use. technology adoption model also called as UTAUT2 [START_REF] Venkatesh | Consumer acceptance and use of information technology: extending the unified theory of acceptance and use of technology[END_REF]. It is defined as "the degree to which a person has formulated conscious plans to perform or not perform some specified future behavior"(Warshaw & [START_REF] Visinand | Le rôle attendu des professionnels RH lors d'un changement organisationnel[END_REF] (p.214). The construct is a mental assessment in which an individual decides whether he or she will act according to their expected plan and describes how near they have come to the decision. It correlates with the rational decision-making process describes in the status quo bias theory. According to the UTAUT2 [START_REF] Venkatesh | Consumer acceptance and use of information technology: extending the unified theory of acceptance and use of technology[END_REF], behavior intention is influenced by external factors such as the effort expectancy, the perceived ease of use and the social influence to name a few.

However, in this study, we expect that due to the post IT implementation scenario in which data was collected it is appropriate to go beyond "perceive value" attitudinal perception in the URM and look at the actual intention to use the technology as a valid substitute measure. Past studies show that incumbent system usage constructs can be directly linked to behavior intention to use new systems [START_REF] Polites | Shackled to the status quo: The inhibiting effects of incumbent system habit, switching costs, and inertia on new system acceptance[END_REF]. Thus, behavior intention to use construct should mediate the relationship between switching costs on the actual use and user resistance of the My Kaaltime. Thus, we posit the below:

H4: Behavior intention to use mediates the relationship between switching cost and IT use.

H5: Behavior intention to use mediates the relationship between switching cost and IT user resistance.

Colleagues are generally the essential point of reference in matters relating to work, which means that through the influence of social norms their opinion about the change to a new IS can heavily influence their comrade's initial perceptions about switching costs and benefits [START_REF] Burnkrant | Informational and normative social influence in buyer behavior[END_REF]. Positive colleague's opinion toward the new IT tool can serve to decrease uncertainty, which can lead to a lower perception of switching costs. Favorable colleague opinion can also benefit in their decision about the net benefit of the new IS-related change which in turn will lead them to have lower switching cost perceptions and higher switching benefit perceptions. Switching benefit refers to "the perceived utility a user would enjoy in switching from the status quo to the new IS" [START_REF] Kim | Investigating user resistance to information systems implementation: A status quo bias perspective[END_REF]. Thus as per the URM theory [START_REF] Kim | Investigating user resistance to information systems implementation: A status quo bias perspective[END_REF] we assert that a favorable colleagues' opinion should positively impact switching benefit perceptions. Thus, we posit the below:

H6: Favorable colleagues opinion will have a negative impact on switching cost H7: Favorable colleagues opinion will have a positive impact on switching benefit

As abovementioned, behavior intention to use is an individual assessment and describes how near an individual has come to the usage decision. Switching benefit perception will provide them the reasons to try to use My Kaalsheet instead of the old systems, as it is a proxy to measure their evaluation that the new tool is considered to provide superior performance than the old tools. Thus, due to the perceived value perception (implied) they should also perceive behavioral intention to use the new HR tool [START_REF] Kim | Investigating user resistance to information systems implementation: A status quo bias perspective[END_REF][START_REF] Polites | Shackled to the status quo: The inhibiting effects of incumbent system habit, switching costs, and inertia on new system acceptance[END_REF]. Hence, a higher-level of switching benefit will increase the behavior intention to use the new HR tool. A positive behavior intention to use the new tool would mean more adoption and use of the tool [START_REF] Venkatesh | User acceptance of information technology: Toward a unified view[END_REF]. Past studies show that incumbent system usage constructs can be directly linked to behavior intention to use new system [START_REF] Polites | Shackled to the status quo: The inhibiting effects of incumbent system habit, switching costs, and inertia on new system acceptance[END_REF]. Thus, we formulate the hypothesis that behavior intention to use has a positive impact on actual use of the new MyKaal sheet tool. Similarly, the behavioral intention to use the technology also would mean that the resistance to the tool is no longer high and therefore their user resistance should be negatively impacted. Thus, we posit the below:

H8: Switching benefits will positively impact behavior intention to use H9: Behavior intention to use will positively impact IT use. H10: Behavior intention to use will negatively impact IT user resistance.

Method

Data Collection, Pre and Pilot Testing

We used survey method to gather data. All items were based on prior literature. We administrated the survey to employees of GOODTECH, Information system department members situated in France through e-mail. Survey is a widely used method and has been depicted is "an excellent vehicle for measuring a wide variety of unobservable data" [START_REF] Bhattacherjee | Social science research: Principles, methods, and practices[END_REF]. All scales were adapted from [START_REF] Kim | Investigating user resistance to information systems implementation: A status quo bias perspective[END_REF] with behavior intention to use scale adopted from [START_REF] Venkatesh | Consumer acceptance and use of information technology: extending the unified theory of acceptance and use of technology[END_REF].

Since survey questions were originally prepared in English, and translated to French, to cater to the target population (Bhattacherjee, 2012) (p73), we also undertook a pre-test for content readability and relevance with the unit manager of the HR IT department of GOOGTECH. This was followed by a pilot test with a working group composed of 5 IT HR domain members who had both English and French language competencies. The French translations were further refined using their help before the survey was distributed to the entire Information Systems department composed of 400 employees within the GOODTECH firm. The participation in the survey was both anonymous and voluntary. The survey remained open for 3 weeks and a total of 103 valid responses were collected for final analysis.

Out of 103 survey responses received, 51 were male and 52 were from female respondents.

The average age of the respondent was 29 years. In terms of their tenure within the company, 56 respondents were under 3 years. 23 respondents were between 4 to 6 years tenure, 5 responents had between 7 to 9 years tenure and 19 respondents had more than 9 years of tenure.

The respondents both managers ( 21) and non-managers (82).

Instrument Validation and Data Analysis

For the data analysis, we used Partial Least Squares (PLS), a latent structural equation modeling technique, as implemented in Smart PLS 3.0, which utilizes a component-based path modeling application (Ringle et al., 2005). PLS avoids the two major problems of inadmissible solutions and factor indeterminacy and thus is appropriate for analyzing complex models with latent variables with small sample sizes as well [START_REF] Fornell | Two structural equation models: LISREL and PLS applied to consumer exit-voice theory[END_REF][START_REF] Pavlou | Psychological contract violation in online marketplaces: Antecedents, consequences, and moderating role[END_REF]. Various prior IS studies have employed PLS and found it to be an effective method for data analysis (Shirish, 2020a;[START_REF] Srivastava | Social presence in virtual world collaboration: An uncertainty reduction perspective using a mixed methods approach[END_REF][START_REF] Teo | Trust and electronic government success: An empirical study[END_REF]. Following the recommended two-stage analytical procedure [START_REF] Anderson | Structural equation modeling in practice: A review and recommended two-step approach[END_REF][START_REF] Hair | Multivariate data analysis[END_REF], the first stage of data analysis evaluates the measurement properties of the constructs, while the second stage examines the structural relationships.

We tested three types of validity: content validity, convergent validity, and discriminant validity. Content validity assesses whether the chosen measures appropriately capture the full domain of the construct [START_REF] Straub | Validation guidelines for IS positivist research[END_REF]. We examined content validity by checking for consistency between the measurement items and the existing literature at the stage of survey design. Convergent validity checks that the indicators for a construct are more correlated with one another than with the indicators of another construct [START_REF] Petter | Specifying formative constructs in information systems research[END_REF]. Most variables were those directly adapted from the reference provided in the original paper [START_REF] Kim | Investigating user resistance to information systems implementation: A status quo bias perspective[END_REF]. Behavior intention to use variable was adapted from [START_REF] Venkatesh | Consumer acceptance and use of information technology: extending the unified theory of acceptance and use of technology[END_REF] and IT use was measured as the actual use of the MyKaalsheet grouped into the frequency of 3 months usage before the survey was taken. Objective inputs from the system were extracted for this variable. The raw data was categorized into a range from 'none' to 'more than 4 times' of HR tool usage in the last three months.

Next, for instrumentation purposes, we tested the measurement model with IT use and IT user resistance as our dependent variables. Factor analysis showed that there is a strong correlation between each of the items and their corresponding construct. This demonstrates convergent validity. We tested convergent validity by examining the composite reliability (CR) and average variance extracted (AVE: the ratio of the construct variance to the total variance among indicators) for the indicators [START_REF] Hair | Multivariate data analysis[END_REF]. We note that 0.70 is the suggested CR threshold for reliable measurement [START_REF] Chin | The partial least squares approach to structural equation modeling[END_REF]. As seen in Table 2, the CR values ranged from .876 to .942, above the threshold. AVE was satisfactory with values ranging from .641 to .891 and thus above the recommended threshold of 0.50 [START_REF] Fornell | Evaluating structural equation models with unobservable variables and measurement error[END_REF] We verified the discriminant validity of the various constructs by checking the square root of the AVE, as recommended by [START_REF] Fornell | Evaluating structural equation models with unobservable variables and measurement error[END_REF]. The values of the square root of the AVEs (shown on the diagonal in Table 3) are all greater than the corresponding inter construct correlations (the off-diagonal entries in Table 3), exhibiting satisfactory discriminant validity.

We also checked the cross-loadings of the items on other constructs, which were quite low indicating discriminant validity. As the sample size of this study was 103, we checked the acceptable smallest sample size to detect the effect of regression analysis at p<0.05 using G*Power [START_REF] Faul | Statistical power analyses using G* Power 3.1: Tests for correlation and regression analyses[END_REF]. The desired power level is typically 0.80, but the researcher performing power analysis can specify the higher level, such as 0.90. The power analysis results for our study revealed the smallest acceptable sample size of 73 for the power level of 0.95 which means that that there is a 95% probability our research will not commit a type II error. As seen in Figure 3, the G power plot

give us the confidence that our sample size of 103 respondents is valid to offer significant results.

Results

Variables For the evaluation of the predictive relevance of the structural model, the Stone and Geisser Q² test was performed using the blindfolding procedure [START_REF] Geisser | A predictive approach to the random effect model[END_REF][START_REF] Stone | Cross-validatory choice and assessment of statistical predictions[END_REF] This study suggests that the constructs of the URM when enriched with adoption specific variable are relevant in post implementation of IT contexts. We therefore address calls made to contextualize IT implementation success and failure factors [START_REF] Dwivedi | Research on information systems failures and successes: Status update and future directions[END_REF] and also contribute to studies that look at dual notion of inhibitor and facilitator to IT use in empirical settings. [START_REF] Cenfetelli | Inhibitors and enablers as dual factor concepts in technology usage[END_REF][START_REF] Tsai | Acceptance and resistance of telehealth: The perspective of dual-factor concepts in technology adoption[END_REF] Third, this study's findings advance the theoretical understanding of the factors that shape resistance and adoption to new HR IT tool. To our knowledge, this is the first study that comprehensively models the antecedents to predict and explain resistance and adoption of HR IT tool amongst IT employees as end users. By enriching the existing URM with adoption variable of behavioral intention of instead of perceived value we provide a parsimonious theory to examine both user adoption and resistance in the context of new HR IT tool implementation. Thus, we offer a robust model that can be used as a foundation to build and develop future models to better understand the HR IT tool use and resistance phenomenon.

Further, we note that organizational support did not have an effect on user resistance and none of the control variables as discussed in the URM model proved relevant in the context of IT employee use of HR tool.

The indirect effect of behavioral intention to use on user resistance and IT use is a significant addition that should motivate future work to uncover additional costs and benefits surrounding behavioral intention to use. In addition, future work could also examine how these perceived costs and benefits vary across different demographic groups. We note that IT department employees, despite their positive attitude towards new technology, can manifest resistance, which can also retard new technology renewals due to tardive user adoption. Thus, companies need to re-consider if IT department members must be considered as change ambassadors and champions when introducing HR IT change within organization. Impact of resistance and adoption need to be further studied [START_REF] Beaudry | Impact of IT User Behavior: Observations through a New Lens[END_REF]. This decision can affect change management strategies and interventions. The amount of training that needs to be provided to IT department employees in order to build their self-efficacy perception may need reevaluation. Researchers should use both qualitative and quantitative techniques to study IT use and resistance. Mixed methods study will be more suited to investigate complex interorganizational information systems implementation initiatives specifically [START_REF] Premkumar | The role of interorganizational and organizational factors on the decision mode for adoption of interorganizational systems[END_REF][START_REF] Valeri | Social network analysis: Organizational implications in tourism management[END_REF]. These technological initiatives can be impacted by national culture particularities and intermediary network dynamics as demonstrated in past studies in the tourism sector (Baggio & Valeri, 2020;Valeri & Baggio, 2020a[START_REF] Shirish | Cognitive-affective appraisal of technostressors by ICT-based mobile workers and their impacts on technostrain[END_REF].

Moreover, we have restricted our model to post implementation phase of technology renewal within a multinational organization in France, which allows us to measure actual IT use through system records. However, empirically testing a partial model that measures user resistance as the only dependent variable may be useful for a pre-implementation phase. In this study, we have not measured the key construct of "perceived value" as proposed in the original model.

Future research should include perceived value and behavior intention to use together and test the model's predictive relevance.

Moreover, since the sample is restricted to only IT savvy employees, it may be interesting to expand this study by incorporating diverse sample to validate the enriched URM model proposed. Although a proper translation of English scales to French was effectuated for the purposes of this study, it may be prudent to use a professional translator when adapting scales from English language to other languages. However, our analysis did not see any measurement error in any of the instruments used in this study, so this issue does not challenge the validity of the findings.

Our study provides a number of implications to practice. First, we provide possible solutions to organizations trying to reduce resistance and increase adoption to new HR IT system.

Switching cost has a direct effect on resistance and IT use. Thus, reducing it may be critical when aiming to eliminate resistance and increase adoption of new tools. This could be achieved by enhancing positive opinions about the change through peer and mentor networks.

Additionally, investing in IT employees' professional development will increase their selfefficacy for change perceptions, which will negatively impact their inertia perceptions and propel them to switch to a new HR tool. Moreover, it is important to emphasize the advantages of the HR tool and to explain the core benefits of this switch at early stages of implementation of the HR tools. Follow up after initial implementation stages to ensure the message percolates will further ensure that the organization intent is well communicated and sustained even after initial implementation phases [START_REF] Beaudry | Impact of IT User Behavior: Observations through a New Lens[END_REF]. This would help in increasing switching benefits and behavior intention to use the tool as passive users looking for workarounds would be convert to a more active user of the new tool. Finally, the findings would help practitioners understand HR tool resistance in the context of a French based large multinational firm in which this study was conducted. We believe that the findings of this study and the proposed model will serve as the first step toward evaluating and devising means to solve one of the long-standing and persistent technology change management problem associated with IT user resistance and adoption issues amongst IT employees specifically.

Figure 1 .

 1 Figure 1. Adapted from[START_REF] Kim | Investigating user resistance to information systems implementation: A status quo bias perspective[END_REF]

  have controlled for organization support in the research model instead of hypothesizing the direct and indirect relationship in this study.

Figure 2 .

 2 Figure 2. Research Model: Enriched User Resistance and Adoption Model

H3:

  Switching cost will positively impact IT user resistance Switching cost as negative psychological reactions can lead to a negative behavior intention to use a technology. Thus, we expect an indirect effect of behavior intention to use on the above relationship of switching cost and actual use already hypothesized. Venkatesh et al. (2003)(p.426) estimates that the reaction of an individual toward the use of IT "affects the formation of their behavioral intention to accept the technology which encourages their active application later". The behavior intention to use construct is derived from the enriched

Figure 3 :

 3 Figure 3: Power Analysis for Determining Sample Size

  . The high Cronbach's alpha values, ranging from .899 to .929 confirm the reliability of the scales for all the constructs. Behavioral Intention to use; COP-Colleagues Opinion; GEN-Gender; OS-Organizational support for change; PO-Position; SEC: Self efficacy for change; SWB-Switching Benefits; SWC-Switching costs; TEN-Tenure; UR-IT User resistance; Use-IT Use

		Cronbach's Alpha rho_A	Composite	Average Variance
				Reliability	Extracted (AVE)
	Age	1.000	1.000	1.000	1.000
	BIU	0.899	0.906	0.937	0.833
	COP	0.808	0.842	0.887	0.725
	GEN	1.000	1.000	1.000	1.000
	OS	0.929	0.939	0.955	0.875
	POS	1.000	1.000	1.000	1.000
	SEC	0.895	0.938	0.934	0.825
	SWB	0.844	0.856	0.894	0.679
	SWC	0.814	0.864	0.876	0.643
	TEN	1.000	1.000	1.000	1.000
	UR	0.858	0.874	0.899	0.641
	Use	0.879	0.902	0.942	0.891
	Note : BIU-

Table 2 :

 2 Measurement Model for Assessment for Reflective Constructs

  Note : BIU-Behavior Intention to use; COP-Colleagues Opinion; GEN-Gender; OS-Organizational support for change; PO-Position; SEC: Self efficacy for change; SWB-Switching Benefits; SWC-Switching costs; TEN-Tenure; UR-IT User resistance; Use-IT Use

	UR	0.099	-0.626	-0.488 0.024	-0.227	-0.058	-0.235 -0.296	0.670	0.087	0.801
	Use	-0.159	0.563	0.386	0.020	0.268	-0.056	0.345	0.287	-0.417	-0.143	-0.416	0.944
		Age	BIU	COP	GEN	OS	PO	SEC	SWB	SWC	TEN	UR	Use
	Age	1.000
	BIU	-0.185	0.912
	COP	-0.217	0.679	0.851
	GEN	-0.189	0.023	0.110	1.000
	OS	-0.066	0.411	0.414	0.074	0.936
	PO	-0.307	-0.055	-0.006 0.147	0.095	1.000
	SEC	0.014	0.430	0.305	-0.060	0.388	-0.003	0.908
	SWB	-0.240	0.636	0.402	0.085	0.442	0.148	0.328	0.824
	SWC	0.136	-0.467	-0.353 0.035	-0.191	-0.070	-0.376 -0.211	0.802
	TEN	0.802	-0.129	-0.137 -0.075	-0.021	-0.285	0.059	-0.200	0.027	1.000

Table 3 :

 3 Fornell-Larcker Criterion

Table 4 :

 4 Structural Model Results

  We are also able to predict 52 percent of the behavioral intention to use which is depended on switching costs and switching benefits perceptions. The reading of the a French context. Second, this study helps in strengthening the theory on IT user resistance by examining the original research model in a different environment such as the HR IT department in France[START_REF] Dennis | A Replication Manifesto[END_REF]. Replicating the URM in a new context shows that this model, if appropriately modified, could be adapted to explain resistance as well as adoption of technologies in mandatory use of newly implemented information systems in post implementation stages as well. Thus, the enriched user adoption and resistance model expands the ambit of prior literature in user resistance by offering a valid theoretical framework to understand user resistance and adoption in post implementation stages of technological renewals or other technology change management initiatives in organizations.

	. The
	blindfolding test, which was conducted with omission distance equals to 7 (the recommended
	number), revealed that all Q² values of the endogenous variables were greater than zero. A
	Positive Q² values provide evidence of the predictive relevance despite the small sample size
	used in this study.
	The R² values allows us to conclude that behavior intention to use via switching cost and
	switching benefits and controls can explain together 59 percent of IT user resistance and 35
	percent of IT use.

  [START_REF] Craig | The IT identity threat: A conceptual definition and operational measure[END_REF]. It will be interesting to examine in future research how this variable may either directly or as a moderator impact switching cost and switching benefits expounded in the enriched post adoption URM model amongst IT professionals. Researchers have called for a more nuanced explanation of the bias perceptions in post implementation phases, this model should be further expanded to include other pertinent variables such as loss aversion, regret avoidance and anchoring effects[START_REF] Lee | Examining the use of status quo bias perspective in IS research: need for re-conceptualizing and incorporating biases[END_REF].Before moving on to practical implications of the study. We believe that we need to list out certain limitations of this study. The findings of this study are very context dependent and domain dependent focused on specific end users from a large France corporation. Further studies should to test the enriched model both prior to technology renewal and post technology renewals.

	Social climate in which the change is introduced is another crucial element to conduct further
	research. The findings show that implementers can rely on colleague's opinion for successful
	technology renewals in HR IT domain. Moreover, our findings reveal that demographic
	indicators such as age, gender, position, tenure are not significant, in explaining HR IT tool use
	or resistance. Finally, the study offers partial validity to URM model variables from a French
	HR tool implementation context.
	Future research needs to examine the role individual level differences when examining dual
	focus models. Particularly it will be interesting to look at individual level technology framing
	of IT department employees to know if they will perceive the change as positive or negative

[START_REF] Shirish | Cognitive-affective appraisal of technostressors by ICT-based mobile workers and their impacts on technostrain[END_REF]

. Moreover, recent research has tried to integrate social, task-related, and personal factors of resistance by understanding how IT identity threat can cause IT resistance (

Table 4 allows us to conclude that all hypothesis proposed in this study are proven. Table 4 and 5 provides the path coefficient values of all the relationship and their significant level supporting all our proposed hypotheses from H1 -H10. Further, we note the indirect effects of the variable behavior intention to use on IT use and IT user resistance with β and t values -1.56**(3.821) and .150**(3.032) respectively are significant. Thus, we can conclude there is a mediation to support hypotheses H4 and H5 in the model. Behavior intention to use partially mediates the relationship between switching costs and IT use and IT user resistance behavior.

Hypotheses Proposed β Results

H1: Self efficacy for change will negatively impact switching cost.

-0.296** Supported

Implications, Limitations and Future Research Directions

This study makes key contributions to IS and organizational change management research.

First, by providing a conceptual replication of the comprehensive theoretically grounded model of URM, we are addressing the need for more replication studies in the IS field [START_REF] Dennis | A Replication Manifesto[END_REF][START_REF] Samhan | Switching to Electronic Health Record Systems: A Replication of the User Resistance Model[END_REF]. The replication allowed us to offer partial validity to the URM model. We provide cross-cultural validity to the model and its measurement items in

Appendix 1: Key Research on IT use and resistance in Information Systems Domain

Perspective Source Domain Maturity IT adoption related [START_REF] Barki | Information system use-related activity: an expanded behavioral conceptualization of individual-level information system use[END_REF][START_REF] Beaudry | Understanding user responses to information technology: A coping model of user adaptation[END_REF][START_REF] Compeau | Computer self-efficacy: Development of a measure and initial test[END_REF][START_REF] Davis | Perceived usefulness, perceived ease of use, and user acceptance of information technology[END_REF][START_REF] Moore | Development of an instrument to measure the perceptions of adopting an information technology innovation[END_REF][START_REF] Taylor | Understanding information technology usage: A test of competing models[END_REF][START_REF] Venkatesh | User acceptance of information technology: Toward a unified view[END_REF] Highly Mature (Several validations and follow up work have been undertaken, which includes contextual developments) IT resistance related [START_REF] Craig | The IT identity threat: A conceptual definition and operational measure[END_REF][START_REF] Ferneley | Resist, comply or workaround? An examination of different facets of user engagement with information systems[END_REF][START_REF] Kahneman | On the interpretation of intuitive probability: A reply to Jonathan Cohen[END_REF][START_REF] Kim | Investigating user resistance to information systems implementation: A status quo bias perspective[END_REF][START_REF] Lapointe | A multilevel model of resistance to information technology implementation[END_REF][START_REF] Marakas | Passive resistance misuse: overt support and covert recalcitrance in IS implementation[END_REF][START_REF] Markus | Power, politics, and MIS implementation[END_REF][START_REF] Selander | Cynicism as user resistance in IT implementation[END_REF] Relatively Mature (Several new concepts continue to emerge and core models continue to be validated)

Dual focus [START_REF] Beaudry | Impact of IT User Behavior: Observations through a New Lens[END_REF][START_REF] Cenfetelli | Inhibitors and enablers as dual factor concepts in technology usage[END_REF][START_REF] Tsai | Acceptance and resistance of telehealth: The perspective of dual-factor concepts in technology adoption[END_REF][START_REF] Van Offenbeek | Towards integrating acceptance and resistance research: evidence from a telecare case study[END_REF] and the current study.

Emerging (Research is limited and fragmented)


Keywords: Strecker reaction, free energy landscape, ab initio molecular dynamics, glycine, prebiotic synthesis TOC graphical entry

The amino acids synthesis from elementary precursors in abiotic conditions is traditionally described according to the Strecker reaction, thoroughly invoked to justify the observation of amino acids in extraterrestrial samples, and their emergence in the primordial Earth. To this day, however, a quantitative microscopic description of the mechanism, thermodynamics and kinetics of the multi-step Strecker reaction is still lacking. In the present work we tackle this study by adopting a state-of-the-art ab initio computational approach, combining an efficient scheme of exploration of the relevant chemical networks with a rigorous determination of the underlying free energy and transition states. We determine the step-by-step chemical pathway from "Strecker precursors" to glycine in solution, and calculate the corresponding full free energy landscape. Our results agree well with the scarce available experimental data, and complete them, thus providing the first end-to-end study of this complex reaction, a crucial bottleneck for the emergence of life.

ceived enormous attention since the Miller experiments in the 1950's, [START_REF] Miller | A Production of Amino Acids Under Possible Primitive Earth Conditions[END_REF][START_REF] Miller | The mechanism of synthesis of amino acids by electric discharges[END_REF] becoming one of the major issues in prebiotic chemistry and origin of life studies 3 . However, the variety of geochemical environments in which amino acids may have appeared, also including extraterrestrial ones, makes the identification of accurate and realistic synthetic pathways for their formation extremely challenging. Amino acids formation environments may have included for instance meteorites, water vapour-rich volcanic eruptions, interstellar media, meteorites, or high-velocity cometary impacts [START_REF] Pizzarello | Non-racemic amino acids in the Murray and Murchison meteorites[END_REF][START_REF] Walker | Carbon dioxide on the early Earth[END_REF][START_REF] Holland | The chemistry of the atmosphere and oceans-(v. 1)[END_REF][START_REF] Johnson | The Miller volcanic spark discharge experiment[END_REF][START_REF] Bernstein | Racemic amino acids from the ultraviolet photolysis of interstellar ice analogues[END_REF][START_REF] Sandford | Prebiotic astrochemistry and the formation of molecules of astrobiological interest in interstellar clouds and protostellar disks[END_REF][START_REF] Ioppolo | A non-energetic mechanism for glycine formation in the interstellar medium[END_REF][START_REF] Ferus | One-pot hydrogen cyanide-based prebiotic synthesis of canonical nucleobases and glycine initiated by high-velocity impacts on early Earth[END_REF] . This complexity is enhanced by the number of molecular species, possibly present in the early Earth, which could have been precursors in amino acid synthesis, including (but not restricted to) water, ammonia, hydrogen cyanide, carbon dioxide, molecular nitrogen, carbon monoxide, methane, molecular hydrogen.

Ever since the seminal Miller experiment, the observed spark-discharge-driven synthesis of amino acids was preceded by the appearance, in the aqueous solution in contact with the gas phase, of reaction intermediates such as aldehydes and cyanide. [START_REF] Miller | A Production of Amino Acids Under Possible Primitive Earth Conditions[END_REF] This observation led to interpret Miller experiments, and in general the prebiotic synthesis of amino acids, in terms of the "Strecker-cyanohydrin" multi-component reaction [START_REF] Strecker | Ueber einen neuen aus Aldehyd-Ammoniak und Blausäure entstehenden Körper[END_REF] (see figure 1). This synthesis involves water, formaldehyde, cyanide and one catalytic ammonia to lead to glycine, the simplest amino acid, but also larger amino acids starting from larger aldehydes. Miller studies further supported the Strecker mechanism hypothesis, [START_REF] Miller | The mechanism of synthesis of amino acids by electric discharges[END_REF] and gave, to some extent, thermodynamics and kinetics experimental data to benchmark the Strecker synthesis of glycine. [START_REF] Van Trump | The Strecker Synthesis and Its Prebiological Importance[END_REF] However, recent crucial analysis of meteorite content and experimental work stressed that (i) β-and γ-amino acids are found in meteorites, while Strecker mechanism can explain only αamino acids formation and (ii) formation of amino acids could occur in experiments without cyanide addition (i.e. with only ammonia and aldehyde, hence not through Strecker mechanism). [START_REF] Koga | A new family of extraterrestrial amino acids in the Murchison meteorite[END_REF] Similarly, recent ab initio computer simulations addressed amino acid formation under extreme conditions (intense electric fields, meteorite impacts), suggesting the possible existence of alternative mechanisms. [START_REF] Carrascoza Mayén | Prebiotic Soup Components Trapped in Montmorillonite Nanoclay Form New Molecules: Car-Parrinello Ab Initio Simulations[END_REF][START_REF] Saitta | Miller experiments in atomistic computer simulations[END_REF][START_REF] Martins | Shock synthesis of amino acids from impacting cometary and icy planet surface analogues[END_REF][START_REF] Goldman | Synthesis of glycinecontaining complexes in impacts of comets on early Earth[END_REF] For instance, electric field may allow original redox processes and hydrogen transfers, leading to glycine formation with a formamide intermediate. [START_REF] Saitta | Miller experiments in atomistic computer simulations[END_REF] In the case of meteorite impacts, C-N bonded oligomers may have formed and their decomposition may have led to glycine derivatives. [START_REF] Goldman | Synthesis of glycinecontaining complexes in impacts of comets on early Earth[END_REF] When it comes to milder conditions, on the other hand, accurate quantum chemistry studies were generally focused on solventless static calculations in the low-temperature limit, thus neglecting entropic contributions apart from vibro-rotational harmonic corrections. [START_REF] Rimola | Deep-space glycine formation via Strecker-type reactions activated by ice water dust mantles. A computational approach[END_REF][START_REF] Rimola | Computational study of interstellar glycine formation occurring at radical surfaces of water-ice dust particles[END_REF] Thus, there is a lack of theoretical studies addressing more widespread, non-extreme environments, i.e., synthesis in solution of relevance to hydrothermal vents and parent bodies of meteorites.

Up to now, the Strecker synthesis is therefore the most (if not the only) accepted and studied chemical pathway towards amino acids synthesis in prebiotic conditions. However, a thorough study of the whole pathway, and the quantitative determination of the relevant thermodynamics and kinetics of each elementary step is, quite surprisingly, still lacking. This is particularly true with respect to the kinetics of the fastest chemical steps (the addition and elimination reactions yielding to glycinonitrile, the first experimentally stable intermediate ((4) in fig. 1). In fact, the glycinonitrile synthesis (reactions (1)→( 2), (2)→(3), (3)→( 4)))

occurs quickly on the experimental timescale, thus without allowing isolation/identification of intermediate metastable states. The kinetics of this specific synthesis is determined only indirectly, using e.g. Taft empirical relationship. [START_REF] Ogata | Kinetics of the condensation of some aliphatic aldehydes with ammonia[END_REF][START_REF] Ogata | Equilibrium additions to carbonyl compounds[END_REF][START_REF] Feraud | Study of some condensation reactions of formol with amino acids[END_REF][START_REF] Sander | Equilibria for additions to the carbonyl group[END_REF] Symmetrically, thermodynamic data lack for the rate limiting part of the synthesis, e.g. the nitrile hydration and the amide hydrolysis (reactions (4)→( 5) and (5)→( 6)). To our best knowledge, despite the crucial role of this synthesis in origins of life scenarios, few experimental studies have been undertaken to achieve a full, step-by-step, quantitative description of the kinetics and thermodynamics of the Strecker amino acids synthesis, and even more so in realistic prebiotic conditions.

To "grasp the nettle", we undertook a detailed theoretical study of the chemistry of the Strecker synthesis of glycine. We assessed the free energy differences and barriers involved in this mechanism, and compared them with experimental data. Eventually, we filled existing gaps in experimental data. We determined the full microscopic reaction mechanism, and 2) and (4)→(5), respectively. We characterised the zwitterionic tetrahedral intermediate (TI 5-6 ) as a transient intermediate of reaction (5)→ (6). Proton exchanges may happen through a water molecule relay during the simulations. We emphasise that the origin and the fate of protons are not decided beforehand in simulations but emerge as a result of our unsupervised protocol of pathway exploration.

NC H C H O H (1) NH 3 -CN C H H O H ⊕ NH 2 H (2') OH 2 H 2 ⊕ O H C H H O H NH 2 (2)
thus provided the first quantum-based ab initio framework of this fundamental reaction.

Quantitatively addressing the question of how, in general, chemical products form in solution, starting from given reactants, demands a versatile and efficient theoretical approach.

In fact, it is indispensable to explicitly include the solvent molecules, which are instead often neglected or oversimplified in more standard computational chemistry studies, particularly in the prebiotic context. In this work, we undertake the first-ever (to our best knowledge) step-by-step ab initio study of the Strecker reaction in solution. To this end, we use ab initio molecular dynamics at the Density Functional Theory (DFT) level, including explicitly tens of solvent water molecules, thus simulating realistic solvation at a realistic concentration of 0.7 mol/L for initial formaldehyde, hydrogen cyanide, or final glycine.

In addition to the cost due to the explicit inclusion of the solvent, a foremost limiting factor in the predictive power of ab initio simulations is represented by the enormous gap between the experimental time scales and the ones that can be simulated. To tackle the time scale issue, we have developed an approach [START_REF] Pérez-Villa | Prebiotic chemistry and origins of life research with atomistic computer simulations[END_REF] based on state-of-the-art enhanced sampling techniques, combined with a flexible definition of the reaction coordinates (collective variables (CVs)) based on the topology of the atomic network. Our method, which includes path-based CVs, [START_REF] Branduardi | From A to B in free energy space[END_REF] has been successfully employed to study chemical reactions in the past, generally limited to a single or to isolated elementary acts. [START_REF] Pietrucci | Formamide reaction network in gas phase and solution via a unified theoretical approach: Toward a reconciliation of different prebiotic scenarios[END_REF][START_REF] Pietrucci | Hydrothermal decomposition of amino acids and origins of prebiotic meteoritic organic compounds[END_REF][START_REF] Pérez-Villa | Synthesis of RNA nucleotides in plausible prebiotic conditions from ab initio computer simulations[END_REF][START_REF] Cassone | Synthesis of (d)-erythrose from glycolaldehyde aqueous solutions under electric field[END_REF] This approach handles the mechanistic analysis in a fully agnostic way, as, for a given elementary act, only the reactants and the products are constrained. Therefore, no input about possible transition states is given, and the system is thus free to find the most favourable way to react. In addition, our description takes the solvent into account, leaving the system free to choose which water molecules might interact with the solute and, for example, exchange H + /OH -with it. Here we deploy our approach for the first time to a complex multi-step synthesis, and a very meaningful one, as the Strecker reaction in aqueous solution. The technical details are described in the Methods section. In order to introduce our results, we first represent, in figure 2, the transition states with the two highest activation free energies: nitrile hydration and amide hydrolysis. It is worth noting how explicit solvent molecular dynamics gives structural details about solvation that (i) are out of reach of current experimental methods and (ii) show fine and specific solvent/transition state interactions that are crucial for a realistic quantitative description.

We note for instance that the negative charge on the nitrile moiety, due to the nucleophilic attack of water, is stabilised by a strong H-bond solvation, as shown by the short (1.4 Å) hydrogen-nitrogen distance in figure 2(a).

Concerning amide hydrolysis to glycine, the metadynamics exploration yielded an unexpected mechanism, with the concerted addition of an hydroxyde anion and the departure of an ammonia molecule as shown in figure 2(b). The mechanism expected from literature proceeds instead via a well-known tetrahedral intermediate. [START_REF] O'connor | Acidic and basic amide hydrolysis[END_REF] However, umbrella sampling simulations in the barrier region display fast interconversion, on a picosecond timescale, between the concerted transition state and the tetrahedral intermediate, resulting in the "volcano"-like shape of the free energy profile in figure 3(g), the intermediate lying within the shallow minimum at s ≈ 0.6. This observation strengthens our results, as our optimisation of the reaction pathways was able to find, unsupervisedly, both the actual transition state, and the close-by tetrahedral intermediate.

We present in the following the full outcome of our study, i.e. the accurate quantitative free energy landscape for the Strecker reaction in aqueous solution. We calculate the free energy level for each (metastable) intermediate state, and the activation free energy for each elementary act of the mechanism.

In the following, we analyse the overall reaction by focusing on two main steps, the synthesis of glycinonitrile (steps (1) to ( 4)) and then the pathway to glycine (steps (4) to ( 6)), and we compare to (sparse) available experimental data whenever possible. Before starting, we underline that when comparing data from different sources, the formaldehyde hydration reaction must be considered: [START_REF] Zavitsas | Reversible hydration of formaldehyde. Thermodynamic parameters[END_REF] All values presented in this paper consider bare formaldehyde as displayed in figure 1, state (1).

H 2 CO + H 2 O H 2 C(OH) 2 ,with ∆ r H -• aq = -8.4 kcal/mol, ∆ r S -• aq = -13 cal/mol/K, ∆ r G -• aq = -4.5 kcal/mol.
For the multi-step reaction (1) (4), we report a cyanide addition mechanism that proceeds via a protonated imine (iminium), consistent with the mechanism proposed in the experimental literature. [START_REF] Van Trump | The Strecker Synthesis and Its Prebiological Importance[END_REF] We note that the experimental difference of activation parameters of the forward and backward reactions in literature [START_REF] Van Trump | The Strecker Synthesis and Its Prebiological Importance[END_REF] is not equal to the thermodynamic difference ∆ r G -• aq ((1) (4)), because the rate limiting steps are not the same in both directions.

The experimental activation parameters for the overall reaction (1) (4) are actually "effective" data, since elementary acts (1) (2'), to (3) (4) are confounded in experiments. The effective experimental activation free enthalpy is ∆G ‡ ef f ective ((1) (4))= 10 kcal/mol. [START_REF] Van Trump | The Strecker Synthesis and Its Prebiological Importance[END_REF] Few experimental data exist on this global result, which makes difficult a detailed comparison to our numerical value. Our observed rate limiting step for the overall process (1)→(4) has a barrier of 15 kcal/mol (elementary act (2')→( 2)). The 5 kcal/mol discrepancy is quite satisfying considering the typical PBE-DFT error, 33 see below. Values next to metastable and transition states are our umbrella sampling free energies relatively to (1), in kcal/mol, except for state (6'), that takes literature acido-basic equilibrium data into account, since simulations led to non-zwitterionic glycine and ammonium (6).

Another relevant experimental difficulty in this reaction concerns the addition of ammonia to formaldehyde and the imine formation without hydrogen cyanide (1)→(3). Ammonia and formaldehyde indeed spontaneously lead to a polycyclic oligomer, the so-called hexamine. [START_REF] Kua | Free energy map for the co-oligomerization of formaldehyde and ammonia[END_REF][START_REF] Ogata | The kinetics of the reaction of formaldehyde with ammonia[END_REF] As a consequence, the authors of reference [START_REF] Ogata | The kinetics of the reaction of formaldehyde with ammonia[END_REF] gave only Taft-type estimate for kinetics of the bare ammonia to formaldehyde reaction. [START_REF] Ogata | Kinetics of the condensation of some aliphatic aldehydes with ammonia[END_REF][START_REF] Ogata | Equilibrium additions to carbonyl compounds[END_REF] Another experimental work yields an Arrhenius activation energy of 4.5 kcal/mol for the low temperature aminomethanol formation on ice. [START_REF] Bossa | NH2CH2OH thermal formation in interstellar ices contribution to the 5-8 µm region toward embedded protostars[END_REF] Furthermore, a recent computational study [START_REF] Kua | Free energy map for the co-oligomerization of formaldehyde and ammonia[END_REF] adopting an implicit solvent approach studied the free energy differences and barriers for ammonia addition to formaldehyde (corresponding to (1)→(2) in this work) and the subsequent imine formation reaction (corresponding to (2)→(3)), calculating for the latter one a rate limiting barrier of 21.6 kcal/mol. This value is significantly worse than ours in comparison to experiments, thus confirming the importance of adopting an explicit solvent approach. For the second part of the glycinonitrile (4) formation, experimental kinetic data are provided in Ref. [START_REF] Van Trump | The Strecker Synthesis and Its Prebiological Importance[END_REF] The decomposition reaction (NH 2 )CH 2 (CN) (NH + 2 )CH 2 +CN -, opposite of reaction (3) (4), has an experimental activation free enthalpy of 27 kcal/mol. Our computed value is 26 kcal/mol, in excellent agreement. Other data about cyanide addition to imine (3)→(4) rely upon gas-phase calculations or small size solvent clusters (three water molecules [START_REF] Koch | A theoretical study of the formation of the aminoacetonitrile precursor of glycine on icy grain mantles in the interstellar medium[END_REF] ). This reference proposes a rate limiting barrier of 35 kcal/mol for (4)→(3), again significantly worse than ours in comparison to experiments. Furthermore, this reference [START_REF] Koch | A theoretical study of the formation of the aminoacetonitrile precursor of glycine on icy grain mantles in the interstellar medium[END_REF] has shown dramatic effect of explicit water molecules addition on the calculated activation barriers, supporting our fully explicit solvent description.

For the pathway leading from glycinonitrile to glycine, in the Strecker mechanism, the main experimental difficulties are twofold: (i) the high activation barriers hamper equilibrium uncatalyzed studies in neutral water, and (ii) the equilibrium is strongly displaced towards products, which makes the nitrile detection difficult. [START_REF] Tewari | Thermodynamics of the hydrolysis reactions of nitriles[END_REF][START_REF] Guthrie | Hydration of nitriles: An examination in terms of no barrier theory[END_REF] The precise thermodynamics of nitrile hydration and of the subsequent amide hydrolysis is therefore an open question. It is generally considered that nitrile hydration is favoured thermodynamically and proceeds through a tautomeric amide intermediate (imidic acid), [START_REF] Van Trump | The Strecker Synthesis and Its Prebiological Importance[END_REF][START_REF] Tewari | Thermodynamics of the hydrolysis reactions of nitriles[END_REF] and that the amide hydrolysis to carboxylic acid is thermodynamically disfavoured. Our results are consistent with this general knowledge (see steps (4)→( 5) and ( 5)→( 6) figure 4). Furthermore, for nitrile hydration to amide, the water addition step is known to be rate limiting compared to the tautomerisation step, also in agreement with our results (compare barriers (4)→(5') and

(5')→( 5) in figure 4). Again, since quantitative results are lacking, our study fills these important gaps in the literature. In particular, our explicit solvent approach is crucial to reveal, with respect to literature, [START_REF] Guthrie | Hydration of nitriles: An examination in terms of no barrier theory[END_REF] that the thermodynamically relevant sub-step of the nitrile hydration is the water addition and not the imidic acid/amide tautomeric equilibrium (compare free energy levels of species (4), ( 5) and (5')).

Kinetic data, on the other hand, are available for glycinonitrile hydration from Ref. [START_REF] Van Trump | The Strecker Synthesis and Its Prebiological Importance[END_REF] glycinonitrile hydration has experimental activation free enthalpies of 29 kcal/mol and 20.5 kcal/mol, under acid limit mechanism or basic limit mechanism, respectively. Our calculated value is 23 kcal/mol, consistently with experiments. In fact, the theoretical transition state is characterised by a water molecule close to a unprotonated nitrile (see figure 2 The glycinamide hydrolysis second-order kinetic parameters are also given in the case of both acid limit mechanism or basic limit mechanism. [START_REF] Van Trump | The Strecker Synthesis and Its Prebiological Importance[END_REF][START_REF] Zavoianu | Structure and reactivity of nitriles and thioamides-alkanine hydrolysis of some niriles and of corresponding thioamides[END_REF] The acid-catalysed activation free enthalpy is 25 kcal/mol, while it is only 19.5 kcal/mol in the basic case. In our simulation of the elementary act (5)→( 6), the mechanism corresponds to the acid-catalysed limit mechanism (addition of water and ammonia leaving group). The calculated barrier is 31 kcal/mol, that compares quite well with the 25 kcal/mol experimental result, within the typical PBE-DFT errors. [START_REF] Riley | Critical assessment of the performance of density functional methods for several atomic and molecular properties[END_REF] The full comparison of our results to the few existing experimental thermodynamics data is summarized in table 1. We made the approximation, common in condensed phase chemistry, that PV terms in enthalpy undergo small variations compared to energy variations, due to the small molar volumes of condensed phases. Thus, (free) enthalpy differences can be approximately compared to (free) energy differences. The total cumulative error on the free energy difference between our calculations and the experimental data for the overall synthesis is 24 kcal/mol, which results from the error accumulation on the 7 elementary acts studied.

If one examine these discrepancies in details, the free energy differences between two states reported in experimental papers are: ∆ r G -• ((1)→( 2))=4 kcal/mol, ∆ r G -• ((2)→(3))=-5.5 kcal/mol, ∆ r G -• ((1)→( 4))=-13/-16 kcal/mol.

The corresponding values herein computed are:

∆ r G -• ((1)→(2))=-3 kcal/mol, ∆ r G -• ((2)→(3))=3
kcal/mol, ∆ r G -• ((1)→( 4))=-23 kcal/mol. In other words, these discrepancies are only respectively 7, 8, and 7/10 kcal/mol, which is reasonable (at most approximately two H bonds [START_REF] Markovitch | Structure and energetics of the hydronium hydration shells[END_REF] ), and largely within the typical PBE-DFT error on heat of formation, of about 10 kcal/mol. [START_REF] Riley | Critical assessment of the performance of density functional methods for several atomic and molecular properties[END_REF] The global -24 kcal/mol error on ∆ r G -• ((1)→( 6)) can be explained by the PBE-DFT overestimation of this specific reaction enthalpy, by comparing database gas phase formation enthalpies from experiments [START_REF] Linstrom | The NIST Chemistry WebBook: A chemical data resource on the internet[END_REF] and PBE-DFT. [START_REF] Johnson | Computational chemistry comparison and benchmark database[END_REF] Using the best available basis sets of Pople-type and Dunning-type (resp. 6-311+G(3df,2p) and aug-cc-pVDZ) in database [START_REF] Johnson | Computational chemistry comparison and benchmark database[END_REF] for our system with the PBE functional, the glycine Strecker synthesis enthalpy reaction errors are respectively -22 and -19 kcal/mol in gas phase compared to experiments. [START_REF] Linstrom | The NIST Chemistry WebBook: A chemical data resource on the internet[END_REF] This intrinsic DFT discrepancy appears to explain most of the present work error.

We remark the importance of careful, systematic assessment of the reaction steps for the prebiotic synthesis of biological building blocks, since the complexity of chemical networks starting from small organic compounds grows quicker than exponentially with the number of consecutive reactions, as pointed out by a recent high impact experimental study of the amino acids synthesis in complex mixtures, [START_REF] Islam | Prebiotic selection and assembly of proteinogenic amino acids and natural nucleotides from complex mixtures[END_REF] as well as recent screening study of prebiotic networks. [START_REF] Wo Los | Synthetic connectivity, emergence, and self-regeneration in the network of prebiotic chemistry[END_REF] However, this kind of studies provide only plausible mechanistic networks and not their quantitative free energy characterisation. In this context, quantitative studies like the present one are needed to understand why some compounds have been selected, and which pathway could actually lead to them.

Table 1: For state (4) we indicate two values for its free energy difference with (1) since use of calculated ∆ r H -• aq and ∆ r S -• aq from [START_REF] Van Trump | The Strecker Synthesis and Its Prebiological Importance[END_REF] gives ∆ r G -• ((1)→( 4))=-13 kcal/mol, while direct extrapolation from temperatures close to 300 K in the same source gives ∆ r G -• ((1)→( 4))=-16 kcal/mol. Reference 46 retained -13 kcal/mol from. [START_REF] Van Trump | The Strecker Synthesis and Its Prebiological Importance[END_REF] We felt giving the experimental value most suitable to the temperature we used is simulations was relevant, and it gives an idea of the error that can be expected from literature data. [START_REF] Van Trump | The Strecker Synthesis and Its Prebiological Importance[END_REF][START_REF] Feraud | Study of some condensation reactions of formol with amino acids[END_REF][START_REF] Sander | Equilibria for additions to the carbonyl group[END_REF] , c [START_REF] Van Trump | The Strecker Synthesis and Its Prebiological Importance[END_REF][START_REF] Ogata | Kinetics of the condensation of some aliphatic aldehydes with ammonia[END_REF][START_REF] Ogata | Equilibrium additions to carbonyl compounds[END_REF] , d [START_REF] Van Trump | The Strecker Synthesis and Its Prebiological Importance[END_REF][START_REF] Zavitsas | Reversible hydration of formaldehyde. Thermodynamic parameters[END_REF][START_REF] Moutou | Equilibrium of α-aminoacetonitrile formation from formaldehyde, hydrogen cyanide and ammonia in aqueous solution: Industrial and prebiotic significance[END_REF] , e [START_REF] Linstrom | The NIST Chemistry WebBook: A chemical data resource on the internet[END_REF][START_REF] Smirnov | The enthalpies of solution and solvation of glycine in mixed water-formamide solvents at 298.15 K[END_REF][START_REF] Svec | Vapor Pressures of Some α-Amino Acids[END_REF][START_REF] Takagi | Vapor pressure of molecular crystals. XIII. Vapor pressure of α-glycine crystal. The energy of proton transfer[END_REF][START_REF] Locke | Effect of solvation on the acid/base properties of glycine[END_REF][START_REF] Haberfield | What is the energy difference between H2NCH2CO2H and+ H3NCH2CO2-?[END_REF] In this work we tackled a fully ab initio study of the end-to-end Strecker reaction in aqueous conditions, by using an explicit solvent description and a state-of-the-art approach for the exploration of chemical networks, the unsupervised identification of best pathways, and the accurate determination of relative free-energies, activation barriers, and transition states. In accomplishing this challenging task, we obtained results in very good agreement with the scarce and sparse experimental data, typically focused on specific elementary steps of this complex, 7-step reaction, filling the experimental gaps. In particular, disclosing relative free energy values for all elementary acts in an explicitly simulated complex medium opens perspective in terms of comparison to actual prebiotic relevant systems. Similar simulations may allow for instance to interpret meteoritic abundances, where thermodynamic equilibrium can be reached. In this context, it is worth noting glycinotirile (4) has been detected in the Sgr B2(N) molecular gas cloud. [START_REF] Belloche | Detection of amino acetonitrile in Sgr B2 (N)[END_REF] The identification of a compound such as amino-amide

(5) as a thermodynamic trap of Strecker synthesis, could be considered another signature of Strecker Mechanism. Our study allows, for the first time, a global and at the same time accurate view of the fundamental Strecker reaction, which is widely regarded as a central tenet in prebiotic chemistry and origins of life studies.

Computational Methods

Born-Oppenheimer Molecular Dynamics (BOMD).

Ab initio molecular dynamics were based on the Density Functional Theory with Perdew-Burke-Ernzerhof functional and Grimme's van der Waals corrections, [START_REF] Perdew | Generalized gradient approximation made simple[END_REF][START_REF] Grimme | Semiempirical GGA-type density functional constructed with a long-range dispersion correction[END_REF] and Martins-Troullier pseudopotentials [START_REF] Troullier | Efficient pseudopotentials for plane-wave calculations[END_REF] for C, N, O and H atoms (with a cutoff of 70 Ry and 10 -5 convergence cutoff for orbitals), with the CPMD software. [START_REF] Hutter | Car-Parrinello molecular dynamics on massively parallel computers[END_REF] BOMD simulations were performed in the canonical ensemble (NVT) at a temperature of 300 K , with a time step of 0.48 fs, in a periodically repeated cubic box of 13.4 Å, including 2 carbon, 2 nitrogen, 6 hydrogen, 1 oxygen atoms, and 81 water molecules. The density of the box is therefore 1.058 kg/L, and the concentration is 0.7 mol/L for initial formaldehyde, hydrogen cyanide or final glycine.

Enhanced sampling simulations.

Metadynamics and umbrella sampling were performed with the PLUMED free energy plugin. [START_REF] Bonomi | A portable plugin[END_REF] The former approach was employed for discovery of pathways, the latter for precise free energy profile determination. We used path-based collective variables s and z . [START_REF] Branduardi | From A to B in free energy space[END_REF] The s coordinate represents the progress along a putative pathway defined as a sequence reference structures. The z coordinate represents the distance from the putative pathway. For path-based collective variables definition, we used a topological metric based on coordination patterns, suited for chemical reactions in solution. [START_REF] Pietrucci | Formamide reaction network in gas phase and solution via a unified theoretical approach: Toward a reconciliation of different prebiotic scenarios[END_REF][START_REF] Pietrucci | Hydrothermal decomposition of amino acids and origins of prebiotic meteoritic organic compounds[END_REF][START_REF] Pérez-Villa | Synthesis of RNA nucleotides in plausible prebiotic conditions from ab initio computer simulations[END_REF] Metadynamics simulations were performed with only two reference structures, corresponding to reactant and products. To identify transition states, we extracted a set of configurations from metadynamics trajectories close to the putative transition state. Starting from such configurations, we launched independent short unbiased BOMD trajectories and we verified whether they fell into reactants and products (committor analysis). A transition state is identified when approximately half of the trajectories are committed to both reactants and products.

To resolve more precisely the transition pathways, we used additional reference structures (12 in total including reactants and products), extracted from unbiased committor analysis trajectories, to define path-based collective variables for umbrella sampling. The latter technique was applied to each elementary reaction by restraining s at different values with parabolic potentials along reaction pathways. 30 to 60 windows were used for each elementary reaction.

Free energy profiles were eventually computed with two different codes, by A. Grossfield 58 and J. Goings 59 based respectively on Weighted Histogram Analysis Method and Multistate Bennett Acceptance Ratio. Statistical error bars were determined by cutting every umbrella sampling trajectory in four parts: the two last parts were used to determine free energy profiles, while the convergence error is estimated as the difference between these two profiles.

Typical statistical errors are of about 1 kcal/mol, smaller than DFT error.

Each metadynamics simulation lasted about 30 ps, committor analysis trajectories 3 ps, and umbrella sampling trajectories 15 ps or more. The global cost for an elementary act is therefore dominated by umbrella sampling, corresponding to about 600 ps in the case of 40

  (a) Nitrile hydration transition state, step (4)→(5'). ∆F ‡ = 23 kcal/mol. (b) Amide hydrolysis transition state, step (5)→(6). ∆F ‡ = 31 kcal/mol.

Figure 2 :

 2 Figure 2: Representative transition state structures for the reaction steps with the largest barriers. The geometries are extracted from umbrella sampling simulations, and the distances displayed are average values.

Figure 3 :Figure 4 :

 34 Figure 3: Umbrella sampling free energy profiles (blue) and error bars (red) for each elementary act. The tetrahedral intermediate (TI 5-6 ) is also shown. Relative free energies are indicated with respect to the Strecker reactants. Error bars are estimated from block analysis.

  (a)), which is intermediate between the two literature limit mechanisms, and consistent with a barrier comprised between the two limiting values.

Acknowledgement

The authors thank Charles Liotta (Gerogia Tech) and Ramanarayanan Krishnamurthy (Scripps Institute) for carefully and critically reading the manuscript, and for their useful suggestions.

We especially emphasise the role of R. K. remarks in the tetrahedral intermediate identification and characterisation. Calculations were performed on the GENCI-IDRIS French National Supercomputing facility, under grant numbers A0040901387, A0050811069, and A0060901387, A0070811069.

Supporting Information Available: