Multiscale modeling of reaction rates: application to archetypal S_N2 nucleophilic substitutions

Abstract

This work outlines the development and application of a multiscale computational protocol to evaluate reaction rates of elementary reactions in internal natural coordinates.

Towards solvent regulated self-activation of N-terminal disulfide bond oxidoreductase-D

“…This work mainly focuses on the possibility of nucleophile formation in the vicinity of the nDsbD Ox active site, as there have been numerous studies of nucleophile-mediated scission of the S-S bonds using both experimental and computational methods. 18,21,52,[66][67][68][69][70][71][72][73][74] Of note, Dopieralski et al, explored disulfide reduction by OH À using different model systems and reported that S N 2 at S (substitution on one of the sulfur) and a-elimination (proton abstraction from the a-carbon) as energetically comparable and feasible. 18,21 Similar to the cases mentioned above, Tyr 42 O À could also assist in the disulfide bond cleavage (Fig.…”

Parameter free evaluation of SN2 reaction rates for halide substitution in halomethane

“…Following the approach presented previously, 1 the relevant dynamics for the (slow) reactive event is described with just one reaction coordinate, s , which is defined as a function s = s ( R ), where R is the set of all of the coordinates of the system. In practice, s is built only from a subset of the coordinates of the atoms participating to the reaction.…”

“…Interpreting s as a “slow” coordinate and considering the rest of the coordinates as a thermal bath, one obtains the Fokker–Planck equation for the probability density P ( s , ṡ , t | s 0 , ṡ 0 ,0) of finding the system with reaction coordinate s and velocity ṡ at time t , if it was in ( s 0 , ṡ 0 ) at time 0. It is convenient to apply the change of coordinates x = s with μ the inertia associated to s , 1 k B the Boltzmann constant, and T the absolute temperature. The Fokker–Planck equation in the set ( x , v ) readswhereIn the latter equation, the streaming frequency and the collision frequency ω c = ξ / μ have been introduced together with the Maxwell–Boltzmann equilibrium probability densitywith and u ( x ) = U ( s )/ k B T .…”

“…To build the reaction coordinate as a linear combination of selected internal coordinates of the atoms, our protocol would normally require to perform at this stage two short molecular dynamics simulations constraining the system to fluctuate around the reactants and the products states. 1,20 However, in the cases studied in this work the mapping between the IRC and the reaction coordinate was made simply following the observations that (i) the nucleophile and the leaving groups possess only traslational degrees of freedom, and (ii) the geometry of the reaction is well defined, i.e. the nucleophile approaches the halomethane along the same direction of the carbon-halogen bond on the side of the hydrogen atoms.…”

“…In a previous work, 1 we introduced a multiscale computational protocol to evaluate the reaction rates of elementary reactions in condensed phases within the Kramers formalism. The method consists in (i) computing the energy profile using the intrinsic reaction coordinate (IRC) method at density functional theory (DFT) level, (ii) performing short molecular dynamics simulations of the reactants and products states to build the reaction coordinate, s , thus mapping the IRC to s , (iii) evaluating the friction coefficient along the reaction coordinate with a hydrodynamic model, and (iv) merging all the collected information to parametrize Kramers equation to compute the reaction rate under the assumptions of high activation energy and moderately high to high friction.…”