Formamide reaction network in gas phase and solution via a unified theoretical approach: Toward a reconciliation of different prebiotic scenarios Fabio Pietrucci1 and Antonino Marco Saitta Institut de Minéralogie, de Physique des Matériaux et de Cosmochimie, Université Pierre et Marie Curie, Sorbonne Universités, CNRS, Muséum National d’Histoire Naturelle, Institut de Recherche pour le Développement, UMR 7590, F-75005 Paris, France Edited by Jerrold Meinwald, Cornell University, Ithaca, NY, and approved October 19, 2015 (received for review July 7, 2015) Increasing experimental and theoretical evidence points to form- electric field can induce the barrierless (spontaneous) formation amide as a possible hub in the complex network of prebiotic of formamide and formic acid from a CH4, CO, NH3,H2O, and chemical reactions leading from simple precursors like H2,H2O, N2, N2 mixture in the condensed phase, and under the same condi- NH3, CO, and CO2 to key biological molecules like proteins, nucleic tions, formamide in turn gives birth to more complex organic acids, and sugars. We present an in-depth computational study of molecules including glycine (14). In this context, understanding the formation and decomposition reaction channels of formamide the thermodynamics (free energy differences) and kinetics im- by means of ab initio molecular dynamics. To this aim we intro- plied in basic reactions of prebiotic relevance is key to assess the duce a new theoretical method combining the metadynamics sam- likelihood of the different scenarios put forward in the literature. pling scheme with a general purpose topological formulation of Computational approaches are a formidable complement to collective variables able to track a wide range of different reaction experiments in this field because they exploit the fundamental mechanisms. Our approach is flexible enough to discover multiple laws of quantum mechanics to study chemical reactions, interpret pathways and intermediates starting from minimal insight on the experimental results, and predict novel mechanisms. systems, and it allows passing in a seamless way from reactions in However, contemporary computational physical chemistry is gas phase to reactions in liquid phase, with the solvent active role dominated by gas-phase calculations at zero temperature, with CHEMISTRY fully taken into account. We obtain crucial new insight into the effects due to temperature, pressure, and chemical environment interplay of the different formamide reaction channels and into relegated to approximated extrapolations. For instance, our knowl- environment effects on pathways and barriers. In particular, our edge of reaction dynamics in condensed phases is far from complete results indicate a similar stability of formamide and hydrogen cy- (15, 16), despite the fact that water is a polyvalent molecule, known anide in solution as well as their relatively facile interconversion, to participate also in formamide chemistry under different roles, thus reconciling experiments and theory and, possibly, two differ- including as a stabilizer through hydrogen bonds, as an efficient ent and competing prebiotic scenarios. Moreover, although not acid–base bifunctional catalyst, and as a coreactant (17). Addi- explicitly sought, formic acid/ammonium formate is produced as tional effects should also be considered, including vibrational an important formamide decomposition byproduct in solution. energy dissipation upon birth of exothermic products or solute trapping into finite-lifetime cages affecting its diffusion and re- chemical reactions | free energy landscapes | ab initio molecular dynamics | activity (16, 18, 19). The large number of possible configurations formamide | prebiotic scenarios [already including few water molecules (17)] together with the strong anharmonicity of liquids naturally calls for methods like ery different environments have been suggested as possible MD that include from the start the finite-temperature dynamics. Vcradles for the emergence of biomolecules, including a pri- mordial liquid soup (1), rarified gaseous interstellar clouds (2, 3), Significance liquid–solid interfaces at hydrothermal conditions (4), and the extreme case of impact sites of meteorites and comets (5). Bio- The qualitative and quantitative description of chemical reac- chemically relevant reactions can be fueled by a range of different tions is a formidable problem. Determining pathways, ener- energy sources, and a large number of possible chemical reactions getics, and kinetics requires costly accurate quantum approaches. and reaction paths are suggested to have played an important role Typically, this amounts to a simplification of gas-phase reactions in the process leading simple molecules to form small organic into elementary steps, which, in turn, are usually directly trans- molecules and, from them, biological monomers and polymers. lated in solution. The topology-based method hereby presented Among such small organic molecules, formamide is assuming allows instead an unbiased exploration of both gas-phase and an ever more central role in prebiotic chemistry research, as re- aqueous-phase reactions. Its application to formamide, a center- cently shown in experiments mimicking some of those origins of piece of prebiotic chemistry, unveils very different reaction net- life scenarios, such as laser sparks (6), UV light (7), proton irra- works between gas and solution regimes, indicating, in the liquid diation (8), or shock waves (as in meteorite impacts) (9). The main phase, new pathways, intermediates, and products. The new reason for such strong interest in formamide, besides its ubiq- scheme allows us also to demonstrate the comparable relative uitousness in the solar system, is its chemical flexibility: it can be stability of formamide, hydrogen cyanide, and formic acid, thus formed from (or, conversely, dissociated into) different molecular contributing insight to a heated current debate in the prebiotic species that represent fundamental building blocks, including H2, chemistry community. H2O, NH3, CO, HCN, HNCO, and HCOOH (10, 11). The bar- riers for these different processes lie in a relatively narrow range, Author contributions: F.P. and A.M.S. designed research, performed research, and wrote providing many synthetic directions. Additionally, as has been also the paper. showed experimentally and computationally, formamide could give The authors declare no conflict of interest. rise to all classes of biomolecular monomers, from amino acids This article is a PNAS Direct Submission. to nucleic acids to sugars (12, 13). 1To whom correspondence should be addressed. Email: [email protected]. For example, inspired by the classic Miller experiments, recent This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. ab initio MD (AIMD) simulations demonstrated that an intense 1073/pnas.1512486112/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1512486112 PNAS Early Edition | 1of6 Downloaded by guest on September 29, 2021 P N −λ ½ ð Þ f ke D R t , Rk ð Þ = Pk=1 s t N , [1] f −λD½RðtÞ, Rk′ k′=1e ! XNf 1 −λ ½ ð Þ ð Þ = − D R t , Rk z t λ log e , [2] k=1 where s represents the progress along a pathway defined through an ordered ... sequence of atomic configurations R1, R2, , RNf , whereas z isameasureofthe distance from the pathway itself. This class of variables proved crucial to obtain free energy landscapes of a variety of processes including gas-phase chemical reactions with concerted mechanisms (33–35) and transformations of carbon nanostructures (36). The key ingredient of path collective variables, determining their effectiveness in a given problem, is the definition of distance DðRðtÞ, RkÞ between the atomic configuration at time t and the kth reference structure. In this work we introduce h i X 2 ½ ð Þ = ð Þ − k D R t , Rk CIS t CIS , [3] Fig. 1. Construction principle of topological path collective variables. The IS connectivity patterns of reactants and products are represented by tables where CIS is the coordination number between atom I of species (element) S′ having individual, nonhydrogen atoms on rows and atomic species (the set and all atomsP J of species S, defined by means of a smooth switching function: of all atoms of a given element) on columns. Arrows indicate changes of ð Þ = ½ − ð ð Þ= 0 ÞN=½ − ð ð Þ= 0 ÞM 0 CIS t J∈S 1 RIJ t RSS′ 1 RIJ t RSS′ . The parameter RSS′ depends coordination numbers; however, all other matrix elements are free to on the two species because, e.g., a C–H bond is shorter than a C–C bond. We change as well thanks to the flexibility of path collective variables (see text). remark that apart from the latter parameters, the sole inputs needed to construct the collective variables are the coordination patterns of the re- actant and product species (and possibly other intermediates) as in Fig. 1. We From a prebiotic perspective, it is necessary to have a compar- used metadynamics both in the fixed Gaussian height and in the well-tem- ative understanding of reaction networks in different environments pered variants (37). The duration of each simulation was between 50 and (gas or condensed phase, with different solvents and also interfaces 200 ps, and we estimate that free energy surfaces have a statistical precision with minerals) and at different conditions (T, P, irradiation, shock of about ±2 kcal/mol by comparing bias profiles at different times and across waves, etc.), eventually embracing also nonequilibrium scenarios,