Stepwise Hydration of 2-Aminooxazole: Theoretical Insight into the

Article pubs.acs.org/JPCA

Stepwise Hydration of 2‑Aminooxazole: Theoretical Insight into the Structure, Finite Temperature Behavior and Proton-Induced Charge Transfer F. Calvo,*,† M.-C. Bacchus-Montabonel,‡ and C. Clavaguéra§ †

LiPhy, Université Grenoble Alpes and CNRS UMR 5588, 140 Avenue de la Physique, 38402 St Martin d’Hères, France ILM, Université Lyon I and CNRS UMR 5306, Université de Lyon, 43 Bd du 11 Novembre 1918, F69622 Villeurbanne Cedex, France § LCM, CNRS, Ecole Polytechnique, Université Paris Saclay, 91128 Palaiseau, France ‡

ABSTRACT: It was recently suggested that 2-aminooxazole (AO) could contribute to the formation of RNA nucleotides on primitive earth. In this article we have considered by means of computational modeling the influence of microhydration on the structural and spectral properties of this potential prebiotic molecule. The stable structures of AO(H2O)n were obtained first by sampling the potential energy landscapes of clusters containing up to n = 20 water molecules, using a simple but reasonably accurate force field and replica-exchange molecular dynamics simulations. Through reoptimization using an explicit description of electronic structure at the level of density functional theory with the M06-2X functional, the formation energies, ionization energies and electron affinities were determined in the vertical and adiabatic treatments, as well as vibrational and optical spectra covering the far-IR, mid-IR, and lower part of the UV ranges. The results generally show a clear segregation between the aminooxazole solute and the water molecules, a water cluster being formed near the nitrogen and amino group side leaving the hydrocarbon side dry even at temperatures corresponding to the liquid state. The spectral signatures generally concur and show distinct contributions of the solute and solvent, spectral shifts to lower energies being in agreement with earlier calculations in bulk solvent. We have also investigated the importance of microhydration on the charge transfer cross section upon collision with a proton, thereby extending an earlier investigation on the bare AO molecule. The presence of water molecules generally reduces the propensity for charge transfer at small sizes, but the influence of the solvent steadily decreases in larger droplets.

1. INTRODUCTION

One critical issue with biomolecular compounds is the evolution of their structure and properties during their transfer into the biological aqueous medium. In the recent decades, mass spectrometric methods began to address such questions directly from the gas phase, with the solute of interest being hydrated in a stepwise manner one water molecule at a time.18,19 Such studies are difficult because the different contributions of the various intra- and intermolecular interactions must be disentangled from one another, further taking into account the natural ruggedness of the potential energy landscapes of such complex molecules. Despite such difficulties, advances in experimental methods supported by appropriate computational modeling have jointly led to the determination, with impressive accuracy, of thermochemical and structural properties of biomolecules such as peptides20,21 or sugars,22,23 revealing for instance how polypeptides become more stable in their zwitterionic form once coated with a sufficient number of solvent molecules.24,25 Such results are consistent with theoretical work suggesting that a single but complete hydration shell could be sufficient to preserve the

Prebiotic chemistry has been aiming to understand how precursors of the building blocks of life could be formed and live under extra terrestrial conditions such as the interstellar medium (ISM) or on icy grains.1−4 An increasingly large number of complex organic molecules, notably prebiotic compounds,5,6 have already been identified in the ISM, on comets or even meteorites where amino acids were discovered.7 Among prebiotic molecules, those possibly contributing to the emergence of nucleic acids are essential. Although the RNA world hypothesis is widely accepted8,9 for the earliest stages of life, the direct formation of RNA from ribose and nucleobases fails.10 A reaction sequence leading to RNA from cyanamide and glycolhaldehyde has been recently proposed by Sutherland and co-workers,11 involving 2-aminooxazole as an efficient and selective intermediate under prebiotic conditions. Since this discovery, the 2-aminooxazole molecule has been investigated both experimentally and theoretically,12,13 its formation mechanisms and microwave spectra being notably scrutinized in great details.14−16 The gas-phase chemistry and fragmentation mechanisms of some of its derivatives have also been explored in the laboratory17 again in concern with astrobiological implications. © XXXX American Chemical Society

Received: December 18, 2015 Revised: April 1, 2016

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DOI: 10.1021/acs.jpca.5b12392 J. Phys. Chem. A XXXX, XXX, XXX−XXX

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The Journal of Physical Chemistry A tertiary structure of small proteins.26 Surprisingly, water also plays a role in the condensed phase of biomolecules, phase transitions occurring by varying the humidity having been reported notably for model polypeptides.27 Microhydration of nucleobases from the gas phase has also received some significant attention, as a step toward understanding hydration of the DNA polymer.28−31 In a recent work, the case of uracil was investigated specifically by some of us,32 revealing unexpected hydration patterns that were previously overlooked. Microhydration of 2-aminooxazole has recently been experimentally addressed by Szabla and co-workers,33 who demonstrated the importance of the solvent on the photochemical process experienced by the molecules in the relaxation of πσ* states. In the present contribution, we address specifically 2aminooxazole in the presence of water, with the purpose of determining its preferential hydration sites and the influence of water on its properties by means of computational modeling. Our survey of microhydrated aminooxazole proceeds according to rather conventional protocols, but using state-of-the-art methods throughout its different steps. A relatively simple force field (Amber f f 99) is employed to explore the energy landscapes for compounds containing up to 20 solvent molecules, using quenched replica-exchange molecular dynamics as our main global optimization tool. This approach also gives insight into the finite temperature behavior and possible temperature-induced structural transitions. At a more accurate level of theory, the likely candidates of the lowest energy configurations are refined using an explicit account of their electronic structure, here based on density-functional theory (DFT) with the M06-2X global-hybrid meta-GGA functional. The combination of Amber f f 99 with this functional was found to perform surprisingly well in the case of microhydrated uracil when compared against alternative electronic structure methods, including MP2 and CCSD(T).32 Besides structural and thermodynamical characterization, the spectroscopies of the microhydrated aminooxazole molecule were determined in the vibrational and optical ranges, neglecting anharmonic effects in this first report. An other property we have considered here is the response of microhydrated aminooxazole to the collision of an impinging proton. While radiation damage to biomolecules is generally thought of originating mainly from high-energy photons, it can also be caused by secondary particles generated along the ionizing radiation track such as low-energy electrons, ions or radicals.34,35 Such processes are obviously important under astrophysical environments, where spatial radiation or ion bombardment naturally occur.36 Different processes can affect the molecular target once it is excited, leading to its ionization and its eventual fragmentation.37−39 Charge transfer (CT) from the projectile to the target is a major source of decay, and here we restrict the study to the case of colliding protons, which are by far the most abundant ions in space, particularly in ionized clouds (HII regions). The theoretical methodology used to determine proton transfer cross sections relies on a well established framework using a molecular description of the collision, which has been successfully used for a variety of biomolecular compounds40 including sugars,41,42 nucleobases32,43 and, more recently, the bare aminooxazole molecule itself.44 Our results generally indicate that the hydration pattern preferentially proceeds on the hydrophilic amino side through the formation of increasingly large water clusters, and is stable

even above the melting point. The mid-IR spectrum of the microhydrated compounds shows non trivial size effects that reflect the specific hydrogen-bond network of the water cluster partly connected to the amino terminus of aminooxazole. Above about 6 water molecules, the vibrational spectrum becomes mostly crowded due to the contribution of the solvent. In the optical range, the ππ* excitation at 6.23 eV14,15 becomes gradually shifted to lower energies in the presence of water, in agreement with the results of Szabla and co-workers using bulk (continuum) models.14 The specific contributions of the solvent become clear already above 5 water molecules. Finally, charge transfer from a colliding proton appears to have an effect mostly at very low hydration levels, with a few water molecules actually reducing the cross section relative to bare aminooxazole. However, the charge transfer efficiency appears reduced for the molecule adsorbed on a hexagonal ice model at high collision energies. The article is organized as follows. The various computational methods employed in this work are detailed in the next section. The static and finite temperature results are presented and discussed in section 3, followed by the spectroscopic characterization of aminooxazole at various hydration levels. The charge transfer response of these compounds to a colliding proton is discussed next, with successively the effects of solvent size, temperature and finally the possible role of an ice surface rather than a free water cluster.

2. METHODS A rather broad set of computational chemistry methods has been employed to determine the stable structures of microhydrated aminooxazole at zero and finite temperature, their vibrational and optical spectra and their collisional response to an impinging proton. In what follows we denote the aminooxazole molecule simply by AO, referring to its microhydrated complexes by AO(H2O)n where n is the number of water molecules, or by 2-aminooxazole@(H2O)n when brevity is not needed. 2.1. Exploration of Energy Landscapes. As usual for high-dimensional molecular systems, we employ a hierarchical approach to determine low-energy conformations by combining a numerically inexpensive force field with an efficient sampling algorithm, followed by the refinement at a chemically more accurate description with an explicit account of electronic structure. Here, following our earlier work on microhydrated uracil,32 the Amber f f 99 force field45 was chosen for its reasonably good accuracy when compared against DFT/M062X calculations.46 RESP atomic charges on the AO molecule required for the electrostatic component of the interactions were determined using this functional with the cc-pVTZ basis set, using the Gaussian09 software package.47 Water molecules are described here with the TIP3P model. Replica-exchange molecular dynamics (REMD) simulations were carried out to sample the potential energy landscapes of the microhydrated compounds having up to 20 molecules, using a geometrically distributed ladder of temperatures having 32 rungs between 25 and 250 K. Each replica was propagated for 1 ns with a time step of 0.5 fs, occasional exchanges between the configurations from two random adjacent trajectories being attempted every 1 ps. Local minimization of configurations periodically saved along all trajectories was then systematically performed to yield a database of local minima, among which the lowest-energy structure is hoped to be found. If the global minimum (GM) changed after this quenching step, a new B


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2.3. Charge Transfer Cross Sections in Proton Collisions. Charge transfer may proceed as the evolution of the quasi-molecular ion/target collisional system considering a one-dimensional reaction coordinate for the approach of the proton toward the biomolecule.40 As very fast processes are concerned, the collision dynamics may be treated in the framework of the sudden approximation hypothesis assuming that vibrational and rotational motions are frozen during the collision time. Semiclassical collision dynamics was developed with the EIKONXS program.52 As shown in previous comparison with quantum wave packet simulations,53 this approach provides correct results in a wide range of collision energy from electronvolts to kiloelectronvolts.54 Charge transfer is highly anisotropic, yet it is hardly feasible to take into account all possible orientations of the proton toward the different clusters. Since the CT process was shown previously41,43,55 to be significantly enhanced in the perpendicular geometry, we have considered, as earlier in the case of microhydrated uracil,32 the approach of the proton to be predominantly perpendicular to the oxazole ring. Molecular calculations were performed with the MOLPRO code56 at the state-averaged CASSCF level of theory using the 6-31G** basis set for all atoms. The active space includes the five highest valence orbitals and the 1s proton orbital. In order to develop calculations at the same level of theory for 2aminooxazole and water clusters, ECP2sdf effective core potentials57 were used for C, N, and O atoms and lowestenergy orbitals were frozen. Nonadiabatic radial coupling matrix elements gKL(R) = ⟨ΨK|∂/∂R|ΨL⟩ were determined by the finite difference technique:58

REMD simulation was initiated from this GM and the quenching analysis repeated, until the most stable structure no longer needed updating. This procedure usually stopped after 3 iterations for the smallest sizes n < 12, whereas 5 iterations were usually needed in the range 12 ≤ n ≤ 20. Additional (but not extensive) REMD simulations were carried out using the AMOEBA polarizable force field,48 but the candidate structures obtained with Amber f f 99 turned out to be the lowest after refining using an explicit description of electronic structure. In addition to locating stable structures, the REMD simulations performed in the last iterations provided information about the finite temperature behavior at thermal equilibrium. Here we have considered only the heat capacity Cv(T) = ∂U/∂T, where U(T) is the internal energy as a function of temperature, as the main thermodynamical observable of interest to characterize possible structural transitions. The heat capacity was obtained by standard histogram reweighting by processing the potential energy distributions gathered along all REMD trajectories.49 2.2. Quantum Chemical Calculations. For each system, the 20 lowest local minima obtained with the force field were reoptimized at the DFT/M06-2X/cc-pVTZ level of theory, the most stable configuration being kept for further analysis. The formation energy corresponding to stepwise hydration was obtained as the difference in total electronic energy upon adding one water molecule in the most stable configuration: ΔEform(n) = E[AO(H 2O)n + 1] − E[AO(H 2O)n ] − E[H 2O]

(1)

No attempt was made to evaluate the thermodynamical equivalent quantity at 300 K, since this temperature would not be physically meaningful for such weakly bound compounds in the gas phase. Local optimizations were also carried out for the cationic and anionic systems in order to determine the electron affinities and ionization energies, both vertical and adiabatic. For these calculations, and especially in the case of anionic systems, the possibly diffuse nature of the excess electron lead us to employ the aug-cc-pVTZ basis instead up to n = 10, and aug-cc-pVDZ above this size. The lowest spin state was always exclusively considered. The infrared spectra in the mid- and far-IR ranges covering 0−4000 cm−1 were determined for all neutral compounds from the same DFT calculations in the double harmonic calculation, using a scaling factor of 0.95 in the mid-IR range. For comparison, the vibrational spectrum of the pure largest water cluster was also determined by locally optimizing the AO(H2O)20 complex without the AO molecule. Additional calculations were performed to determine the lowest energy part of the electronic spectra, again repeating the calculations for the pure water cluster. Using the DFT/M062X/cc-pVTZ geometries, electronic spectra were obtained by TD-DFT calculations in the Tamm−Dancoff approximation50 at the DFT/M06-2X/aug-cc-pVDZ level. The addition of diffuse functions was necessary to reproduce CASPT2/ CASSCF excitation energies for the bare AO molecule.15 For the clusters containing up to 10 water molecules, the spectra were computed also with the aug-cc-pVTZ basis set without any quantitative change on the results. The Orca program was used for the determination of the electronic spectra.51 To characterize the nature of the excited states, difference densities produced by the excitation were computed and visualized.

gKL(R ) = lim ⟨ΨK (R )|ΨL(R + Δ)⟩ Δ→ 0

(2)

where the step Δ was checked to provide an accurate stability of the differentiation procedure. The present calculations used Δ = 0.0012 a.u.

3. RESULTS AND DISCUSSION 3.1. Stable Structures. A selection of nine lowest-energy structures obtained for AO(H2O)n is depicted in Figure 1 for different numbers of water molecules. Overall the hydration pattern for this molecule is rather straightforward, with hydrogen bonding near the nitrogens and no water sticking toward the hydrophilic carbonaceous part of the oxazole cycle. A single water molecule acts as both acceptor and donor of two hydrogen bonds, and if it is placed on the oxygen side, the resulting structure is less stable by 3.86 and 4.39 kcal/mol at the Amber and DFT levels, respectively. This greater stability on the nitrogen side is consistent with the stronger electrostatic potential, which is reflected on the difference in atomic charges used in the force field (−0.13e versus −0.67e) and originating from the DFT calculations themselves. As further solvent molecules are added a water cluster forms and grows, adopting the natural polymorphs of pure water aggregates such as fused cubes or pentagonal rings.59 The solute molecule itself can participate to the completion of the hydrogen bond network, e.g. for n = 6 where it contributes to closing the cubic water cluster. This trend generally agrees with the recent findings of Szabla et al.,33 who also reported a clear segregation between the water molecules and 2-aminooxazole. However, these authors found the water cluster to be preferentially located on the oxygen side of the heterocycle, C


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employed in ref 33., notably those used to generate the structures themselves. As the water cluster grows on the nitrogen side of 2aminooxazole, the hydrogen bonds formed between the solute and the surrounding water appear generally less strong than the intrawater hydrogen bonds, as suggested by the weak disruption of the water network. For instance, at sizes n = 10 and 15, the emerging pentagonal water nanotube is barely altered by the presence of aminooxazole, which prefers to stay outside. Only do larger clusters start to solvate the amino group more clearly, with a noticeable structural change between n = 15 and n = 20, even though the water cluster remains entirely segregated throughout. These results contrast with those obtained with uracil,32 which due to alternating hydrophobic/hydrophilic parts exhibits more complex hydration patterns. It is therefore not surprising that the binding and electronic properties do not markedly depend on size in the present case of aminooxazole. The formation energies, electron affinities and ionization potentials obtained for the lowest-energy structures are given in Table 1 for all microhydrated aminooxazole compounds containing up to 20 water molecules. The formation energy gradually increases from 10.7 kcal/mol for a single added water molecule to 11.9 kcal/mol/molecule at n = 19, with occasional fluctuations that reflect structural changes and special stabilities at zero temperature. It is not our purpose to detail such changes here, however it is important to notice that the steady increase in formation energy confirms the greater importance of water− water interactions relative to aminooxazole-water contributions to binding. At size 10, the use of a smaller basis set contributes to enlarging the formation energy by 0.15 kcal/mol, which should thus be considered as an overestimation for all sizes above 10.

Figure 1. Lowest-energy structures of 2-aminooxazole@(H2O)n for different numbers n of water molecules, n = 1−6 and 10, 15, 20, shown with a common orientation of aminooxazole.

which is at variance with our own results. We believe that these different results are due to the different theoretical methods

Table 1. Formation Energy ΔEform, Vertical and Adiabatic Electron Affinities (EA), Vertical and Adiabatic Ionization Energies (IE) of Microhydrated Aminooxazole, As Obtained from Quantum Chemical Calculations at the DFT/M06-2X/aug-cc-pVTZ Level or DFT/M06-2X/aug-cc-pVDZ Levela

a

number of water molecules

ΔEform ([kcal/mol]/molecule)

vertical EA (eV)

adiabatic EA (eV)

vertical IE (eV)

adiabatic IE (eV)

0 1 2 3 4 5 6 7 8 9 10 10a 11a 12a 13a 14a 15a 16a 17a 18a 19a 20a

0 10.69 10.71 10.23 10.29 10.61 11.12 11.19 11.02 11.19 11.11 11.26 11.42 11.63 11.51 11.51 11.63 11.67 11.72 11.74 11.86 11.73

−0.524 −0.539 −0.494 −0.392 −0.482 −0.388 −0.378 −0.372 −0.341 −0.320 −0.294 −0.421 −0.385 −0.369 −0.340 −0.349 −0.302 −0.259 −0.294 −0.298 −0.311 −0.256

−0.519 −0.530 −0.487 −0.272 −0.430 −0.351 −0.379 −0.372 −0.328 −0.300 −0.267 −0.407 −0.364 −0.348 −0.220 −0.326 −0.268 −0.211 −0.287 −0.099 −0.198 −0.063

8.65 8.63 8.55 8.78 8.69 8.74 8.61 8.51 7.60 8.68 8.65 8.56 8.61 8.60 8.67 8.69 8.67 8.73 8.73 8.36 8.65 8.36

8.14 7.90 7.87 7.63 7.73 7.73 7.61 7.61 7.60 7.41 7.51 7.40 7.52 7.52 7.48 7.45 7.57 7.58 7.39 7.24 7.42 7.23

Structure at the DFT/M06-2X/aug-cc-pVDZ level. D


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the smallest clusters shows that the few water molecules become mobile also at temperatures approaching 150 K. To characterize the melting mechanisms in the microhydrated compounds, we have simply determined the threedimensional density of water around aminooxazole from the REMD trajectories, keeping the solute molecule in a fixed reference frame for computation and visualization of this density. Typical 3D densities obtained as thermal averages from the MD trajectories are shown in Figure 3 for selected systems

The ionization potentials for the bare aminooxazole molecule using density functional theory slightly overestimate the value obtained earlier, at the CASSCF level, by a fraction of eV.44 These quantities also show rather minor variations as the microhydration level increases, except for a drop at size n = 8 corresponding to a special stability of the cation with the cubic water cluster besides the AO molecule. Reducing the basis set at n = 10 leads to a drop of about 0.1 eV for both the vertical and adiabatic ionization energies. Except for the magic cluster at size 8, the significant differences between the vertical and adiabatic ionization energies indicate major rearrangements upon removal of an electron in the system. In contrast, the electron affinities appear rather low with the basis sets employed containing diffuse functions. At the ccpVTZ level, much higher values of 1.5−2.5 eV are obtained with much more significant differences between the vertical and adiabatic results. Such moderate electron affinities, together with the very modest variations between the vertical and adiabatic values, indicate that the extra electron is indeed diffuse around the complex. While cationic clusters undergo strong rearrangements, anionic complexes thus tend to accommodate well with the extra electron. 3.2. Finite Temperature. The variations with temperature of the canonical heat capacities of selected AO(H2O)n systems with n = 1−4, 6, 10, 15, and 20 are depicted in Figure 2. For the

Figure 3. Thermal density of water molecules around 2-aminooxazole, for microhydration with 5, 10, or 18 molecules (from top to bottom) and at equilibrium temperatures of 50, 100, or 200 K (from left to right), as obtained from replica-exchange MD simulations.60

with n = 5, 10, and 18 and at the three temperatures below (50 K), near (100 K), and above (200 K) the melting phase change. At low temperature, the water molecules are essentially localized around the solute and they can be identified almost individually. As the system approaches melting, the density becomes more diffuse with the water molecules making excursions on both faces of the solute. In the two larger clusters, the water molecules are still mostly localized at 100 K. At 200 K, the solvent is liquidlike for all clusters, however the liquid still does not manage to coat the solute and remains on the nitrogen and amino side, leaving the hydrophilic part of aminooxazole dry. At finite temperature, the behavior of microhydrated aminooxazole thus appears as driven by its hydrophilic part, which prevents isotropic solvation. This has important implications in experiments notably relying on the electrospray technique for producing microhydrated compounds: Owing to its strongly hydrophobic part, the aminooxazole solute should be quite difficult to stabilize in water droplets without thermally desorbing. 3.3. Spectroscopic Characterization. From the stable structures locally reoptimized at the DFT level, the vibrational spectra were calculated in the mid- and far-IR ranges in the simple double harmonic approximation. A scaling factor of 0.95 was applied to the mid-infrared range in order to improve the comparison with known experimental positions of hydrogen stretching bands.61 Selected spectra are represented in Figure 4 for various microhydrated clusters with n = 1−4, 6, 10, 15 and

Figure 2. Canonical heat capacity of 2-aminooxazole@(H2O)n for different numbers n of water molecules, as obtained from replicaexchange MD simulations.

smallest systems, this thermal observable displays roughly monotonic variations with temperature with only minor deviations to harmonicity rather than any clear isomerization or phase change. As the number of solvent molecules increases, a broad shoulder in the heat capacity arises at n = 4 and evolves into a clear peak near 150 K indicative of the melting phase change of the water cluster. At this temperature the AO molecule remains essentially rigid with occasional inversion of the amino group. Minor size effects are found on the thermodynamical properties, the transition temperature remaining in the 120−160 K range. Despite not showing any thermal signature, visual inspection of the MD trajectories in E


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1600 cm−1 are perturbed by the aminooxazole molecule which also carries fairly active modes near 1600−1700 −1 corresponding to bendings of the amino group. However, even in the largest cluster considered here these bending modes remain distinguishable from the water bending modes, and could constitute suitable bands to look at in experiments. Likewise we have determined the optical spectra in the UV range from the lowest excitations identified in TD-DFT calculations. Similarly with vibrational spectra, the electronic spectrum has also been determined for the pure water cluster in order to emphasize the role of the aminooxazole solute. The Gaussian-broadened spectra are depicted in Figure 5 for the

Figure 4. Harmonic IR spectra of 2-aminooxazole@(H 2 O) n compounds with various numbers n of water molecules obtained at the DFT/M06-2X/cc-pVTZ level of theory in both the far- and midIR ranges. The spectrum for the bare (H2O)20 cluster is also shown at the top. In the mid-IR range, the frequencies were scaled by 0.95.

20, and for the bare aminooxazole. To get further insight into the relative contributions of the solute and the solvent, the IR spectrum was also determined for the pure 20-water cluster locally reoptimized from its complex with aminooxazole. The 2900−3800 cm−1 range is where hydrogen bond stretchings are most sensitive to the overall structure of the water cluster, the moderately active hydrogen stretching bonds in the bare aminooxazole molecule vanishing rapidly once water molecules are added. Strong size effects are found in this range as the number of waters stepwise varies, as the result of complex hydrogen-bond network patterns. However, spectral crowding becomes clear in the 3200−3500 cm−1 range typical of OH bonds participating to hydrogen bonding already when the number of solvent molecule reaches 10, the active modes exceeding 3700 cm−1 being indicative of free OH stretchings. However, in this region the symmetric stretch of the amino group is also active, hindering a clear identification based on these modes. In the larger clusters, NH2 stretches being often less intense than OH stretches, it would be difficult to distinguish the former. Although the pure water cluster was directly borrowed from the microhydrated compound, differences in the IR spectrum near 3000 cm−1 are noteworthy as the result of perturbations of the hydrogen bond network by the solute. This specific spectral range appears to carry most of the differences between the bare solute, the pure solvent and the microhydrated compounds. It would be interesting to extend these calculations by taking anharmonicities and temperature effects into account to assess whether the spectral range near 3000 cm−1 indeed shows marked differences that convey the interaction between the solute and solvent. In the far-IR range, the spectra vary much more smoothly with increasing number of solvent molecules, the signature of the bare water cluster appearing already at n = 5 with broad lines near 200 and 700 cm−1 typical of hydrogen bond stretch and libration modes, respectively. The bending modes near

Figure 5. Selected electronic spectra of 2-aminooxazole@(H2O)n compounds with various numbers n of water molecules obtained at the DFT/M06-2X/aug-cc-pVDZ level of theory, and corresponding spectrum for the bare (H2O)20 cluster shown at the top. Two density plots are shown for the transitions of the 6-water molecule undergoing excitations of 6.23 eV (upper left) and 8.13 eV (upper right). The πσ* excited states near 5.5 eV are highlighted by a dashed box for n = 4 and 6.

same selection of microhydrated clusters, namely n = 0−4, 6, 10, 15, and 20. The results for the bare molecule are in good agreement with the earlier work by Szabla and co-workers,14,15 in which the lowest bright excited state was found as a ππ* state near 6.25 eV, followed by two excitations closer to 7−7.2 eV affecting the oxazole cycle and corresponding to ring-opening and ring puckering motions. Upon microhydration, aminooxazole keeps the spectral signature of these modes until about 4 water molecules are present. At this stage, the spectral bands begin to show characteristics of pure water cluster with bright excitations near 8 eV, where aminooxazole is not optically active. As the number of water molecules increases, the lowest ππ* excited state shifts to lower energies by about 0.1 eV, which is consistent with earlier calculations by Szabla and coworkers who found a shift of 0.2 eV for bulk hydrated aminooxazole.14 Besides the ππ* state, a πσ* state appears also F


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this stronger effect. In the present case, microhydration always proceeds exclusively on the side of aminooxazole and barely influences proton-induced charge transfer, thereby recovering the behavior of the bare solute. Such analysis is supported by looking at the molecular calculations, which indicate that charge transfer is mainly driven by an excitation from a molecular orbital (MO) located on the target toward the 1s orbital of the incident proton.32 This MO is almost unchanged for 2aminooxazole@(H2O)n with n = 0−6, as can be witnessed from Figure 6, and does not involve much polarization between the solute and the water molecules, at marked variance with the behavior of microhydrated uracil.32 All the results reported in Figure 6 were obtained for frozen molecular structures in their electronic ground state energy minimum, and it is unclear whether they would remain as such at finite temperature, where not only the aminooxazole molecule vibrates, but the hydration pattern also changes. Unfortunately, it is not practical to achieve the same quality thermodynamical sampling of the configuration space with the DFT and Amber f f 99 methods, and we have chosen the latter to supply relevant configurations for further statistical analysis. However, comparing the results obtained for the static DFT structure with those obtained at finite temperature with the force field requires as an intermediate step to also determine the collision cross-section at the equilibrium geometry predicted by the force field. If the calculations are repeated for the bare molecules in the geometry of the force field, the corresponding cross-section also shown in Figure 6 clearly exhibits a significant but essentially constant shift by 1 order of magnitude. This shift is due to the slight constraints exerted on chemical structure, especially the bond lengths, which are obviously not so well described by the force field. Having shown that the cross sections experience a roughly constant shift when the molecules are described by the force field, temperature effects can be evaluated next, assuming the global shift would remain similar in an explicit description of electronic structure. From a small sample of 10 structures borrowed from the REMD trajectory at 250 K and successively separated by 100 ps, the charge transfer cross sections were calculated independently and averaged, the resulting curves being depicted in Figure 7. Two groups of structures can be differentiated within this sample, as highlighted by the use of two line styles on the figure with comparable statistical weight in the MD trajectory. Within each group, variations due to thermal motion amount up to 1 order of magnitude, which is consistent with the effects of changing the potential energy surface on the cross section already noted earlier. These groups mostly differ depending on the orientation of the water molecule relative to the amino group, which points either toward the oxygen or one hydrogen of the solvent molecule. In the former case, water can be both donor and acceptor of hydrogen bonds (as in the global minimum structure), but due to temperature effects can also explore out of plane regions of configuration space. The overall consequence on the charge transfer is rather minor with only some distinguishable shift to higher cross sections. In contrast, water molecules pointing the oxygen away from the amino group tend to less efficient hydrogen bonding and much lower charge transfer cross sections. As the cross section is arithmetically averaged over the 10 configurations of the sample, the global average is shifted to the higher values, although it does not show marked differences with respect to the 0 K reference data for the force field.

in the microhydrated compounds near 5.5 eV, but with a much lesser intensity. We have highlighted it in Figure 5 near the sizes n = 4 and 6, after magnifying the spectra by a factor 5. This state was also reported in ref 33 in the case of a water pentamer lying on the oxygen side of AO. The optical spectrum of microhydrated aminooxazole thus contains the respective signatures of both the solute and solvent, which was somewhat expected as the result of their clear segregation. The hydrogen bonding network connecting the solvent to the solute has a weak influence on the amino NH bond stretch photoexcited mode, with a nearly constant excitation energy near 6.2−6.4 eV. To some extent, the same holds for the ring-opening and ring puckering modes near 7.2 eV, which remain for the microhydrated aminooxazole even containing substantial numbers of water molecules. While the lowest part of the optical spectrum is not dramatically modified by the presence of water, the photodynamics are expected to be much more affected because the different photochemical pathways of hydrogen loss, ring puckering and ring-opening should become sterically hindered by the solvent. 3.4. Proton-Induced Charge Transfer. The charge transfer cross sections for optimized DFT structures are presented in Figure 6 for bare 2-aminooxazole and micro-

Figure 6. Charge transfer cross sections upon proton impact on 2aminooxazole@(H2O)n with various numbers n of water molecules, as a function of collision energy and using DFT optimized geometries. For the bare molecule, the results are also shown for the geometry optimized at the level of the Amber f f 99 force field (FF). The molecular orbitals involved in the charge transfer process are also depicted.

hydrated compounds containing up to 6 water molecules. For comparison, the corresponding cross sections calculated with the bare molecule optimized with the Amber f f 99 force field have been superimposed on this figure. Relatively weak variations are found upon stepwise microhydration of aminooxazole. The charge transfer cross sections are globally reduced for the 2-aminooxazole@(H2O) complex and then oscillate around a mean value for larger compounds. As the number of solvent molecules reaches n = 6, the cross sections have almost recovered the values for the bare molecule, and smoothly increase with increasing energy. This behavior is at variance with uracil, where the details of hydration pattern and especially the hydrogen-bond network were found to influence the charge transfer cross section significantly with varying size,32 the more direct interaction with water causing G


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Figure 7. Charge transfer cross sections upon proton impact on 2aminooxazole@H2O as a function of collision energy and for a small sample of thermally equilibrated geometries at 250 K with geometries produced from the Amber force field. In addition to individual contributions shown as dashed lines, the average is shown with the solid red line and compared to the static results at the frozen T = 0 geometry (solid black line).

Figure 8. Charge transfer cross section upon proton impact on 2aminooxazole@(H2O)n deposited on the surface of hexagonal ice (red line), and compared with the bare molecule with the same orientation with the same geometry (green line) or locally optimized (blue line) all with the Amber force field.

4. CONCLUDING REMARKS The recent interest for the aminooxazole molecule was driven by the potential of this molecule to act as a key intermediate toward RNA synthesis. The ubiquitous presence of water under the conditions where aminooxazole could form suggests that microhydrated aminooxazole could also well occur and show different chemical reactivity. In the present article, we have conducted a broad theoretical survey of the fundamental properties of aminooxazole in contact with a controlled number of water molecules ranging from 0 to 20, and attempted to rationalize various properties at zero or finite temperature. Using a fieldproven methodology based on a numerically efficient force field to scan the potential energy landscapes combined with the refinement of candidate structures within a quantum chemical framework, the microhydration pattern of aminooxazole appears very progressive and proceeds by nucleating and growing a water cluster hydrogen bonded to the nitrogen and amino groups. The water cluster is highly stable against thermal disorder, and the aminooxazole solute remains desorbed on the water nanodroplet even above the melting temperature, presenting its hydrophobic hydrocarbon side away from the cluster. The vibrational spectra, but especially the optical spectra, show clear signatures of this segregation pattern. Likewise the response to proton-induced charge transfer was also found to depend rather poorly on the presence of water, and even on the thermal fluctuations of the solvent due to compensating conformations in the canonical sample. However, extending these calculations to a model of an icy grain revealed a stronger effect that could indicate different chemical reactivities especially at low collision energies. One natural extension of the present work could consider the kinetic stability of the microhydrated complexes and their resistance to evaporation or fragmentation. In particular, due to the surface location of aminooxazole it could desorb before any water molecule evaporates. The computational tools employed in the present article could also be applied to address this issue, e.g., by carring direct molecular dynamics simulations of the evaporation process over limited time scales ranging up to the nanosecond, and extending the predictions to macroscopic time scales using suitable rate theories. Such a time multiscale

Temperature thus has relatively modest effects and does not qualitatively alter the overall behavior of the charge transfer cross section. A contrasted behavior is predicted by considering now the aminooxazole molecule as deposited on the surface of water ice. Reactivity at the surface of icy grains is a challenging but largely open question.62 To evaluate the importance of the ice substrate on the charge transfer experienced by the molecule upon colliding with a proton, we have locally optimized the geometry of aminooxazole on a 6-water ring with fixed oxygen geometry (but mobile hydrogens) corresponding to a basal plane from hexagonal ice. The optimized geometry mainly rotates to present the amino group as an hydrogen bond donor and the nitrogen oxazole as an hydrogen bond acceptor. The oxazole plane is distinctly tilted with respect to the ice basal plane, and in order to disentangle the effects of ice deposition and misorientation from each other the cross sections were also calculated for the tilted (but unrelaxed) molecule in vacuum. The resulting charge transfer cross sections are represented in Figure 8 as a function of collision energy. In this case, the tilted orientation appears to increase the average cross section by about 1 order of magnitude with respect to collisions perpendicular to the oxazole plane [see Figure 6]. More interestingly, contact with the ice surface results in monotonically decreasing variations of the cross sections, which could induce a rather different reactivity of 2-aminooxazole on icy grains with respect to the isolated form. Finally, relaxing the geometry but keeping the same orientation only leads to a global decrease of the cross section similar in magnitude to the one separating the optimized DFT and force field geometries, as seen in Figure 6. These results are consistent with one another and indicate that the different behavior obtained for aminooxazole deposited on hexagonal ice are not merely caused by the specific orientation but also by the contact with the substrate. Obviously those conclusions should be reexamined in the light of a more accurate treatment of the ice surface, taking into account a larger piece of the substrate rather than the six closest molecules imposed by the computational constraints of the dynamical calculations. H


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strategy has been successfully used in the past for related compounds.63 Among the possible extensions of the present work, it would be useful to also address protonated species that are more amenable to accurate experimental characterization through mass spectrometry methods. Protonation is likely to affect mainly the amino group, which should significantly disrupt the hydrogen bonding network and the growth of the water cluster, as well as the entire spectroscopic signatures. Ionic compounds would probably be better modeled using polarizable force fields such as AMOEBA,48 with a small price to pay in terms of statistical convergence. In the light of the role of the water surface on the proton transfer cross section, the chemical reactivity of aminooxazole on hexagonal ice would also deserve more attention. As far as bulk systems are concerned, the structure and equilibrium thermodynamics of 2-aminooxazole in bulk liquid water close to prebiotic conditions should be investigated further, with the purpose of characterizing the size and isotropy of the hydration shells. From the static point of view of the excitation spectrum, it seems relevant to determine the possible changes upon upscaling from a finite cluster in vacuum into the semi-infinite medium. At finite temperature, first-principle molecular dynamics simulations should also shed light onto the stability of aminooxazole on the ice substrate, given that the upper basal plane of hexagonal ice exhibits some degree of proton disorder that was almost entirely neglected here due to our highly local representation of this substrate.

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AUTHOR INFORMATION

Corresponding Author

*(F.C.) E-mail: fl[email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors wish to acknowledge generous computational resources from the regional Pôle Scientifique de Modélisation Numérique in Lyon, the CCIN2P3 in Villeurbanne, and the CCRT/CINES/IDRIS under the allocation 2015[i2015081566] made by GENCI. The authors acknowledge also support from the COST actions TD1308 Life-Origins, CM1204 XLIC, and CM1401 Astrochemical History.

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REFERENCES

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Stepwise Hydration of 2-Aminooxazole: Theoretical Insight into the

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