Competing Reaction Mechanisms of Peptide Bond Formation in Water Revealed by Deep Potential Molecular Dynamics and Path Sampling.

The formation of an amide bond is an essential step in the synthesis of materials and drugs, and in the assembly of amino acids to form peptides. The mechanism of this reaction has been studied extensively, in particular to understand how it can be catalyzed, but a representation capable of explaining all the experimental data is still lacking. Numerical simulation should provide the necessary molecular description, but the solvent involvement poses a number of challenges. Here, we combine the efficiency and accuracy of neural network potential-based reactive molecular dynamics with the extensive and unbiased exploration of reaction pathways provided by transition path sampling. Using microsecond-scale simulations at the density functional theory level, we show that this method reveals the presence of two competing distinct mechanisms for peptide bond formation between alanine esters in aqueous solution. We describe how both reaction pathways, via a general base catalysis mechanism and via direct cleavage of the tetrahedral intermediate respectively, change with pH. This result contrasts with the conventional mechanism involving a single pathway in which only the barrier heights are affected by pH. We show that this new proposal involving two competing mechanisms is consistent with the experimental data, and we discuss the implications for peptide bond formation under prebiotic conditions and in the ribosome. Our work shows that integrating deep potential molecular dynamics with path sampling provides a powerful approach for exploring complex chemical mechanisms.

Prebiotic chemical reactivity in solution with quantum accuracy and microsecond sampling using neural network potentials.

While RNA appears as a good candidate for the first autocatalytic systems preceding the emergence of modern life, the synthesis of RNA oligonucleotides without enzymes remains challenging. Because the uncatalyzed reaction is extremely slow, experimental studies bring limited and indirect information on the reaction mechanism, the nature of which remains debated. Here, we develop neural network potentials (NNPs) to study the phosphoester bond formation in water. While NNPs are becoming routinely applied to nonreactive systems or simple reactions, we demonstrate how they can systematically be trained to explore the reaction phase space for complex reactions involving several proton transfers and exchanges of heavy atoms. We then propagate at moderate computational cost hundreds of nanoseconds of a variety of enhanced sampling simulations with quantum accuracy in explicit solvent conditions. The thermodynamically preferred reaction pathway is a concerted, dissociative mechanism, with the transient formation of a metaphosphate transition state and direct participation of water solvent molecules that facilitate the exchange of protons through the nonbridging phosphate oxygens. Associative-dissociative pathways, characterized by a much tighter pentacoordinated phosphate, are higher in free energy. Our simulations also suggest that diprotonated phosphate, whose reactivity is never directly assessed in the experiments, is significantly less reactive than the monoprotonated species, suggesting that it is probably never the reactive species in normal pH conditions. These observations rationalize unexplained experimental results and the temperature dependence of the reaction rate, and they pave the way for the design of more efficient abiotic catalysts and activating groups.

Adsorption Studies at the Graphene Oxide-Liquid Interface: A Molecular Dynamics Study.

The adsorption of organic aromatic molecules, namely aniline, onto graphene oxide is investigated using molecular simulations. The effect of the oxidation level of the graphene oxide sheet as well as the presence of two different halide salts, sodium chloride and sodium iodide, were examined. The aniline molecule in the more-reduced graphene oxide case, in the absence of added salt, showed a slightly greater affinity for the graphene oxide-water interface as compared to the oxidized form. The presence of the iodide ion increased the affinity of the aniline molecule in the reduced case but had the opposite effect for the more-oxidized form. The effect of oxidation and added salt on the interfacial water layer was also examined.

Unraveling the Role of Charge Patterning in the Micellar Structure of Sequence-Defined Amphiphilic Peptoid Oligomers by Molecular Dynamics Simulations.

Electrostatic interactions play a significant role in regulating biological systems and have received increasing attention due to their usefulness in designing advanced stimulus-responsive materials. Polypeptoids are highly tunable N-substituted peptidomimetic polymers that lack backbone hydrogen bonding and chirality. Therefore, polypeptoids are suitable systems to study the effect of noncovalent interactions of substituents without complications of backbone intramolecular and intermolecular hydrogen bonding. In this study, all-atom molecular dynamics (MD) simulations were performed on micelles formed by a series of sequence-defined ionic polypeptoid block copolymers consisting of a hydrophobic segment and a hydrophilic segment in an aqueous solution. By combining the results from MD simulations and experimental small-angle neutron scattering data, further insights were gained into the internal structure of the formed polypeptoid micelles, which is not always directly accessible from experiments. In addition, information was gained into the physics of the noncovalent interactions responsible for the self-assembly of weakly charged polypeptoids in an aqueous solution. While the aggregation number is governed by electrostatic repulsion of the negatively charged carboxylate (COO-) substituents on the polypeptoid chain within the micelle, MD simulations indicate that the position of the charge on singly charged chains mediates the shape of the micelle through the charge-dipole interactions between the COO- substituent and the surrounding water. Therefore, the polypeptoid micelles formed from the single-charged series offer the possibility for tailorable micelle shapes. In contrast, the polypeptoid micelles formed from the triple-charged series are characterized by more pronounced electrostatic repulsion that competes with more significant charge-sodium interactions, making it difficult to predict the shape of the micelles. This work has helped further develop design principles for the shape and structure of self-assembled micelles by controlling the position of charged moieties on the backbone of polypeptoid block copolymers.

Acids at the Edge: Why Nitric and Formic Acid Dissociations at Air-Water Interfaces Depend on Depth and on Interface Specific Area.

Whether the air-water interface decreases or increases the acidity of simple organic and inorganic acids compared to the bulk is critically important in a broad range of environmental and biochemical processes. However, a consensus has not yet been achieved on this key question. Here we use machine learning-based reactive molecular dynamics simulations to study the dissociation of paradigmatic nitric and formic acids at the air-water interface. We show that the local acidity profile across the interface is determined by changes in acid and conjugate base solvation and that the acidity decreases abruptly over a transition region of a few molecular layers. At the interface, both acids are weaker than in the bulk due to desolvation. In contrast, acidities below the interface reach a plateau and are all the stronger compared to those in the bulk as the surface to volume ratio of the aqueous phase is large, due to the growing impact of the stabilization of the released proton at the surface of the water. These results imply that the measured degree of dissociation sensitively depends on the experimental probing length and system size and suggest a molecular explanation for the contrasting experimental results. The aerosol size dependence of acidity has important consequences for atmospheric chemistry.

A bio-inspired heterodinuclear hydrogenase CoFe complex.

Herein, a new heterobimetallic CoFe complex is reported with the aim of comparing its performance in terms of H2 production within a series of related MFe complexes (M = Ni, Fe). The fully oxidized [(LN2S2)CoII(CO)FeIICp]+ complex (CoIIFeII, LN2S2 2- = 2,2'-(2,2'-bipyridine-6,6'-diyl)bis(1,1'-diphenylethanethiolate), Cp- = cyclopentadienyl anion) can be (electro)chemically reduced to its CoIFeII form, and both complexes have been isolated and fully characterized by means of classic spectroscopic techniques and theoretical calculations. The redox properties of CoIIFeII have been investigated in DMF, revealing that this complex is the easiest to reduce by one-electron among the analogous MFe complexes (M = Ni, Fe, Co). Nevertheless, it displays no electrocatalytic activity for H2 production, contrary to the FeFe and NiFe analogs, which have proven remarkable performance.

Reactive events at the graphene oxide-water interface.

Graphene oxide exhibits interesting reactive events at its interface with water, with water as an active participant. The reactive events are influenced by the level of oxidation of the graphene oxide sheet. The fully oxidized sheet tends to make the interfacial water media acidic leaving the sheet negatively charged, whereas the reduced sheet can form comparatively long lived carbocations as well as split water forming two alcohol groups on the sheet.

Effect of anion identity on ion association and dynamics of sodium ions in non-aqueous glyme based electrolytes-OTf vs TFSI.

Sodium-based rechargeable battery technologies are being pursued as an alternative to lithium, in part due to the relative abundance of sodium compared to lithium. Despite their low dielectric constant, glyme-based electrolytes are particularly attractive for these sodium-based batteries due to their ability to chelate with the sodium ion and their high electrochemical stability. While the glyme chain length is a parameter that can be tuned to modify solvation properties, charge transport behavior, reactivity, and ultimately battery performance, anion identity provides another tunable variable. Trifluoromethanesulfonate (triflate/OTf) and bis(trifluoromethane)sulfonamide (TFSI) are chemically similar anions, which are often used in battery electrolytes for lithium-based batteries. In this paper, molecular simulations are used to examine the differences in ion association and charge transport between sodium salts of these two anions at different salt concentrations in glymes with the increasing chain length. The use of the modified force field developed for NaOTf in glymes for the NaTFSI electrolytes was validated by comparing the TFSI-sodium ion radial distribution functions to the results from ab initio molecular dynamics simulations on 1.5 M NaTFSI in diglyme. While the ion association behavior as a function of salt concentration showed similar trends for both NaOTf and NaTFSI in tetraglyme and triglyme electrolytes, the dominant solvation structures for the two sets of electrolytes are distinctly different in the monoglyme and diglyme cases. The conductivity is impacted by both the ion association behavior in these electrolytes and the non-vehicular or hopping transport of the anions in these systems.

Effect of Oxidation Level on the Interfacial Water at the Graphene Oxide-Water Interface: From Spectroscopic Signatures to Hydrogen-Bonding Environment.

The interfacial region of the graphene oxide (GO)-water system is nonhomogenous due to the presence of two distinct domains: an oxygen-rich surface and a graphene-like region. The experimental vibrational sum-frequency generation (vSFG) spectra are distinctly different for the fully oxidized GO-water interface as compared to the reduced GO-water case. Computational investigations using ab initio molecular dynamics were performed to determine the molecular origins of the different spectroscopic features. The simulations were first validated by comparing the simulated vSFG spectra to those from the experiment, and the contributions to the spectra from different hydrogen bonding environments and interfacial water orientations were determined as a function of the oxidation level of the GO sheet. The ab initio simulations also revealed the reactive nature of the GO-water interface.

Ion Pairing in HCl-Water Clusters: From Electronic Structure Investigations to Multiconfigurational Force-Field Development.

In the bulk, condensed-phase HCl exists as a dissociated Cl- ion and a proton that is delocalized over solvating water molecules. However, in the gas phase, HCl is covalent, and even on the introduction of hydrating water molecules, the HCl covalent state dominates small clusters and is relevant at larger clusters including 21 water molecules. Electronic structure calculations (at the MP2 level) and ab initio metadynamics simulations (at the DFT level) have been carried out on HCl-(H2O)n clusters with n = 2-22 to investigate distinct solvation environments in clusters from covalent HCl structure, to contact ion pairs and solvent-separated ion pairs. The data were further used to train and validate a multiconfigurational force-field for HCl-water clusters that incorporates covalent HCl states into the MS-EVB3.2 formalism. Additionally, the many-body interaction of the Cl- ion with water and the excess proton was modeled by the introduction of two geometric three-body terms that incorporates the dominant many-body interaction in an efficient noniterative manner.

Interfacial Water at Graphene Oxide Surface: Ordered or Disordered?

The graphene oxide (GO)-water interface was simulated using Born-Oppenheimer molecular dynamics (BOMD) simulations with two different functionals, namely, revPBE-D3 and BLYP-D2, as well as a commonly used classical force field, namely, OPLS-AA. A number of different order parameters, including the orientation of the interfacial water molecules near the aromatic region of the GO surface as well as those near the oxygenated defects, were examined and compared. The BOMD interfacial waters are clearly much less structured as compared to the classical force field that shows a strongly ordered interface. Higher-level calculations, namely, symmetry adapted perturbation theory, were performed on representative clusters taken from the BOMD simulation. These calculations revealed not only that a number of conformations have similar interaction energies but also the importance of induction contribution to the interaction energies.

Effect of Monoelectronic Oxidation of an Unsymmetrical Phenoxido-Hydroxido Bridged Dicopper(II) Complex.

A (µ-hydroxido, µ-phenoxido)CuIICuII complex 1 has been synthesized using an unsymmetrical ligand bearing an N, N-bis(2-pyridyl)methylamine (BPA) moiety coordinating one copper and a dianionic bis-amide moiety coordinating the other copper(II) ion. Electrochemical mono-oxidation of the complex in DMF occurs reversibly at 213 K at E1/2 = 0.12 V vs Fc+/Fc through a metal-centered process. The resulting species (complex 1+) is only stable at low temperature and has been spectroscopically characterized by UV-vis-NIR cryo-spectroelectrochemical and EPR methods. DFT and TD-DFT calculations, consistent with experimental data, support the formation of a CuIICuIII phenoxido-hydroxido complex. Low-temperature chemical oxidation of 1 by NOSbF6 yields a tetranuclear complex 2(SbF6)(NO2) which displays two binuclear CuIICuII subunits. The X-ray crystal structure of 2(SbF6)(NO2) evidences that the nitrogen of the terminal amide group is protonated and the coordination of the amide occurs via the O atom. The bis-amide moiety appears to be a non-innocent proton acceptor along the redox process. Alternatively, protonation of complex 1 leads to the complex 2(ClO4)2, as evidenced by X-ray crystallography, cyclic voltammetry, and 1H NMR.

Influence of Asymmetry on the Redox Properties of Phenoxo- and Hydroxo-Bridged Dicopper Complexes: Spectroelectrochemical and Theoretical Studies.

The redox properties and electronic structures of a series of phenoxo- and hydroxo-bridged dicopper(II) complexes have been explored. Complexes (1a-c)2+ are based on symmetrical ligands with bis(2-methylpyridyl)aminomethyl as complexing arms bearing different substituting R groups (CH3, OCH3, or CF3) in the para position of the phenol moiety. Complex 2a2+ is based on a symmetrical ligand with bis(2-ethylpyridyl)aminomethyl arms and R = CH3, while complex 3a2+ involves an unsymmetrical ligand with two different complexing arms (namely bis(2-ethylpyridyl)aminomethyl and bis(2-methylpyridyl)aminomethyl). Investigations have been done by electrochemical and spectroelectrochemical means and correlated to theoretical calculations as this series of complexes offers a unique opportunity of an in-depth comparative analysis. The voltammetric studies have shown that the redox behavior of the dicopper complexes is not influenced by the nature of the solvent. However, the increase of the spacer chain length and the unsymmetrical design induce significant modifications of the voltammetric responses for both oxidation and reduction processes. DFT calculations of the redox potentials using a computational reference redox couple calculated at the same level of theory to reduce systematic errors confirm these results. Ligand contributions to the electronic structure of the different species have been analyzed in detail. The good agreement between experimental and theoretical results has validated the developed calculation method, which would be used in the following to design new dinuclear copper complexes. These studies demonstrate that subtle modification of the ligand topology can significantly affect the redox and spectroscopic properties. In particular, the unsymmetrical design allows the formation of a transient mixed-valent Cu(II)-Cu(III) phenoxo complex detected upon spectroelectrochemical experiments at room temperature, which evolves toward a dicopper (II,II) phenoxyl complex. The latter displays an intense π → π* transition band at 393 nm in the UV-vis spectrum compared to the less intense ligand to metal charge transfer band at 518 nm observed for the mixed-valent Cu(II)-Cu(III) phenoxo complex.

Iron Hydroperoxide Intermediate in Superoxide Reductase: Protonation or Dissociation First? MM Dynamics and QM/MM Metadynamics Study.

Superoxide reductase is a mononuclear iron enzyme involved in superoxide radical detoxification in some bacteria. Its catalytic mechanism is associated with the remarkable formation of a ferric hydroperoxide Fe3+-OOH intermediate, which is specifically protonated on its proximal oxygen to generate the reaction product H2O2. Here, we present a computational study of the protonation mechanism of the Fe3+-OOH intermediate, at different levels of theory. This was performed on the whole system (solvated protein) using well-tempered metadynamics at the QM/MM (B3LYP/AmberFF99SB) level. Enabled by the development of a new set of force field parameters for the active site, a conformational MM study of the Fe3+-OOH species gave insights into its solvation pattern, in addition to generating the two starting conformations for the ab initio metadynamics setup. Two different protonation mechanisms for the Fe3+-OOH intermediate have been found depending on the starting structure. Whereas a possible mechanism involves at first the protonation of the hydroperoxide ligand and then dissociation of H2O2, the most probable one starts with an unexpected dissociation of the HOO- ligand from the iron, followed by its protonation. This favored reactivity was specifically linked to the influence of both the nearby conserved lysine 48 residue and the microsolvatation on the charge distribution of the oxygens of the HOO- ligand. These data highlight the crucial role of the whole environment, solvent, and protein, to describe accurately this second protonation step in superoxide reductase. This is clearly not possible with smaller models unable to reproduce correctly the mechanistically determinant charge distribution.

Room-Temperature Characterization of a Mixed-Valent µ-Hydroxodicopper(II,III) Complex.

Bis(µ-hydroxo)dicopper(II,II) bearing a naphthyridine-based ligand has been synthesized and characterized in the solid state and solution. Cyclic voltammetry at room temperature displays a reversible redox system that corresponds to the monoelectronic oxidation of the complex. Spectroscopic and time-resolved spectroelectrochemical data coupled to theoretical results support the formation of a charge-localized mixed-valent Cu(II,III)2 species.