Q-RepEx: A Python pipeline to increase the sampling of empirical valence bond simulations.

The exploration of chemical systems occurs on complex energy landscapes. Comprehensively sampling rugged energy landscapes with many local minima is a common problem for molecular dynamics simulations. These multiple local minima trap the dynamic system, preventing efficient sampling. This is a particular challenge for large biochemical systems with many degrees of freedom. Replica exchange molecular dynamics (REMD) is an approach that accelerates the exploration of the conformational space of a system, and thus can be used to enhance the sampling of complex biomolecular processes. In parallel, the empirical valence bond (EVB) approach is a powerful approach for modeling chemical reactivity in biomolecular systems. Here, we present an open-source Python-based tool that interfaces with the Q simulation package, and increases the sampling efficiency of the EVB free energy perturbation/umbrella sampling approach by means of REMD. This approach, Q-RepEx, both decreases the computational cost of the associated REMD-EVB simulations, and opens the door to more efficient studies of biochemical reactivity in systems with significant conformational fluctuations along the chemical reaction coordinate.

Solvent Effects on the Menshutkin Reaction.

The Menshutkin reaction is a methyl transfer reaction relevant in fields ranging from biochemistry to chemical synthesis. In the present work, the energetics and solvent distributions for NH3+MeCl and Pyr+MeBr reactions were investigated in explicit solvent (water, methanol, acetonitrile, benzene, cyclohexane) by means of reactive molecular dynamics simulations. For polar solvents (water, methanol, and acetonitrile) and benzene, strong to moderate catalytic effects for both reactions were found, whereas apolar and bulky cyclohexane interacts weakly with the solute and does not show pronounced barrier reduction. The calculated barrier heights for the Pyr+MeBr reaction in acetonitrile and cyclohexane are 23.2 and 28.1 kcal/mol compared with experimentally measured barriers of 22.5 and 27.6 kcal/mol, respectively. The solvent distributions change considerably between reactant and TS but comparatively little between TS and product conformations of the solute. As the system approaches the transition state, correlated solvent motions occur which destabilize the solvent-solvent interactions. This is required for the system to surmount the barrier. Finally, it is found that the average solvent-solvent interaction energies in the reactant, TS, and product state geometries are correlated with changes in the solvent structure around the solute.

Thermal activation of methane by MgO+: temperature dependent kinetics, reactive molecular dynamics simulations and statistical modeling.

The kinetics of MgO+ + CH4 was studied experimentally using the variable ion source, temperature adjustable selected ion flow tube (VISTA-SIFT) apparatus from 300-600 K and computationally by running and analyzing reactive atomistic simulations. Rate coefficients and product branching fractions were determined as a function of temperature. The reaction proceeded with a rate of k = 5.9 ± 1.5 × 10-10(T/300 K)-0.5±0.2 cm3 s-1. MgOH+ was the dominant product at all temperatures, but Mg+, the co-product of oxygen-atom transfer to form methanol, was observed with a product branching fraction of 0.08 ± 0.03(T/300 K)-0.8±0.7. Reactive molecular dynamics simulations using a reactive force field, as well as a neural network trained on thousands of structures yield rate coefficients about one order of magnitude lower. This underestimation of the rates is traced back to the multireference character of the transition state [MgOCH4]+. Statistical modeling of the temperature-dependent kinetics provides further insight into the reactive potential surface. The rate limiting step was found to be consistent with a four-centered activation of the C-H bond, in agreement with previous calculations. The product branching was modeled as a competition between dissociation of an insertion intermediate directly after the rate-limiting transition state, and traversing a transition state corresponding to a methyl migration leading to a Mg-CH3OH+ complex, though only if this transition state is stabilized significantly relative to the dissociated MgOH+ + CH3 product channel. An alternative, non-statistical mechanism is discussed, whereby a post-transition state bifurcation in the potential surface could allow the reaction to proceed directly from the four-centered TS to the Mg-CH3OH+ complex thereby allowing a more robust competition between the product channels.

Sampling reactive regions in phase space by following the minimum dynamic path.

Understanding mechanistic aspects of reactivity lies at the heart of chemistry. Once the potential energy surface (PES) for a system of interest is known, reactions can be studied by computational means. While the minimum energy path (MEP) between two minima of the PES can give some insight into the topological changes required for a reaction to occur, it lacks dynamical information and is an unrealistic depiction of the reactive process. For a more realistic view, molecular dynamics (MD) simulations are required. However, this usually involves generating thousands of trajectories in order to sample a few reactive events and is therefore much more computationally expensive than calculating the MEP. In this work, it is shown that a "minimum dynamic path" (MDP) can be constructed, which, contrary to the MEP, provides insight into the reaction dynamics. It is shown that the underlying concepts can be extended to directly sample reactive regions in phase space. The sampling method and the MDP are demonstrated on the well-known 2-dimensional Müller-Brown PES and for a realistic 12-dimensional reactive PES for sulfurochloridic acid, a proxy molecule used to study vibrationally induced photodissociation of sulfuric acid.

Molecular Determinants for Rate Acceleration in the Claisen Rearrangement Reaction.

The Claisen rearrangement is a carbon-carbon bond-forming, pericyclic reaction of fundamental importance due to its relevance in synthetic and mechanistic investigations of organic and biological chemistry. Despite continued efforts, the molecular origins of the rate acceleration in going from the aqueous phase into the protein is still incompletely understood. In the present work, the rearrangement reactions for allyl-vinyl-ether (AVE), its dicarboxylated variant (AVE-(CO2)2), and the biologically relevant substrate chorismate are investigated in the gas phase, water, and in chorismate mutase. Only the rearrangement of chorismate in the enzyme shows a negative differential barrier when compared to the reaction in water, which leads to the experimentally observed catalytic effect for the enzyme. The molecular origin of this effect is the positioning of AVE-(CO2)2 and chorismate in the protein active site compared to AVE. Furthermore, in going from AVE-(CO2)2 to chorismate, entropic effects due to rigidification and ring formation are operative, which lead to changes in the rate. On the basis of "More O'Ferrall-Jencks" diagrams, it is confirmed that C-O bond breaking precedes C-C bond formation in all cases. This effect becomes more pronounced in going from the gas phase to the protein.

Erratum: Publisher's Note: "Implications of short time scale dynamics on long time processes" (Struct. Dyn. 4, 061507 (2017)].

[This corrects the article DOI: 10.1063/1.4996448.].

OH-Stretching Overtone Induced Dynamics in HSO3F from Reactive Molecular Dynamics Simulations.

The OH-stretch induced dynamics in fluorosulfonic acid (HSO3F) is characterized from a statistically significant number of trajectories using multisurface adiabatic reactive molecular dynamics (MS-ARMD) simulations. The global reactive potential energy surface, which describes H-transfer and HF-elimination, is parametrized at the MP2/6-311G++(2p,2d) level of theory with an accuracy of better than 1 kcal/mol. Excitation along the OH-local mode leads to H-transfer dynamics but elimination of HF is only observed for excitations with ν ≥ 6 for 1 out of 5000 trajectories. This finding differs fundamentally from the situation for vibrationally induced photodissociation of H2SO4 and HSO3Cl, for which, even with excitations of 4 quanta along the OH-stretch mode, elimination of H2O and HCl, respectively, is readily observed on the subnanosecond time scale. RRKM rates for HX-elimination in HSO3X (X = F, Cl) only differ by a factor of 5. The findings from the reactive molecular dynamics simulations together with the RRKM results thus indicate that the origin for a closed HF-production channel is dynamical. This is also consistent with experimental findings for hydrofluoroethanes in shock tubes, which found pronounced non-RRKM behavior.

Implications of short time scale dynamics on long time processes.

This review provides a comprehensive overview of the structural dynamics in topical gas- and condensed-phase systems on multiple length and time scales. Starting from vibrationally induced dissociation of small molecules in the gas phase, the question of vibrational and internal energy redistribution through conformational dynamics is further developed by considering coupled electron/proton transfer in a model peptide over many orders of magnitude. The influence of the surrounding solvent is probed for electron transfer to the solvent in hydrated I-. Next, the dynamics of a modified PDZ domain over many time scales is analyzed following activation of a photoswitch. The hydration dynamics around halogenated amino acid side chains and their structural dynamics in proteins are relevant for iodinated TyrB26 insulin. Binding of nitric oxide to myoglobin is a process for which experimental and computational analyses have converged to a common view which connects rebinding time scales and the underlying dynamics. Finally, rhodopsin is a paradigmatic system for multiple length- and time-scale processes for which experimental and computational methods provide valuable insights into the functional dynamics. The systems discussed here highlight that for a comprehensive understanding of how structure, flexibility, energetics, and dynamics contribute to functional dynamics, experimental studies in multiple wavelength regions and computational studies including quantum, classical, and more coarse grained levels are required.

Nonadiabatic effects in electronic and nuclear dynamics.

Due to their very nature, ultrafast phenomena are often accompanied by the occurrence of nonadiabatic effects. From a theoretical perspective, the treatment of nonadiabatic processes makes it necessary to go beyond the (quasi) static picture provided by the time-independent Schrödinger equation within the Born-Oppenheimer approximation and to find ways to tackle instead the full time-dependent electronic and nuclear quantum problem. In this review, we give an overview of different nonadiabatic processes that manifest themselves in electronic and nuclear dynamics ranging from the nonadiabatic phenomena taking place during tunnel ionization of atoms in strong laser fields to the radiationless relaxation through conical intersections and the nonadiabatic coupling of vibrational modes and discuss the computational approaches that have been developed to describe such phenomena. These methods range from the full solution of the combined nuclear-electronic quantum problem to a hierarchy of semiclassical approaches and even purely classical frameworks. The power of these simulation tools is illustrated by representative applications and the direct confrontation with experimental measurements performed in the National Centre of Competence for Molecular Ultrafast Science and Technology.

HSO3Cl: a prototype molecule for studying OH-stretching overtone induced photodissociation.

Vibrationally induced photodissociation in sulfurochloridic acid (HSO3Cl) is found to be a viable process to form SO3 and HCl from excitations of the OH-stretching overtone starting at νOH = 4. Reactive molecular dynamics simulations on a fully-dimensional potential energy surface fitted to MP2 calculations show that hydrogen transfer and HCl elimination compete with one another on the nanosecond time scale. Excitation with 5 and 6 quanta in the OH-stretch direct elimination of HCl is a dominant process on the several hundred picosecond time scale. At longer times, HCl formation is preceded by intramolecular hydrogen transfer and concomitant excitation of torsional degrees of freedom. As HSO3Cl is a suitable proxy for H2SO4, which is relevant for weather and climate in the upper atmosphere, it is concluded that vibrationally induced photodissociation is a possible mechanism for H2SO4 decomposition. Final state energy distributions for different internal degrees of freedom are predicted which should be observable in laboratory measurements.