Modeling of solvent flow effects in enzyme catalysis under physiological conditions

TL;DR

This paper presents a stochastic model combining analytical and simulation methods to study solvent flow effects on enzyme catalysis under physiological conditions, revealing how solvent dynamics influence reaction times and enzyme motions.

Contribution

It introduces a novel integrated approach using explicit solvent modeling and analytical first passage time densities to analyze enzyme catalysis dynamics.

Findings

Solvent flow facilitates enzyme hinge motions.

Hydrodynamic flow impacts substrate binding times.

Solvent-enzyme coupling significantly affects reaction cycle durations.

Abstract

A stochastic model for the dynamics of enzymatic catalysis in explicit, effective solvents under physiological conditions is presented. Analytically-computed first passage time densities of a diffusing particle in a spherical shell with absorbing boundaries are combined with densities obtained from explicit simulation to obtain the overall probability density for the total reaction cycle time of the enzymatic system. The method is used to investigate the catalytic transfer of a phosphoryl group in a phosphoglycerate kinase-ADP-bis phosphoglycerate system, one of the steps of glycolysis. The direct simulation of the enzyme-substrate binding and reaction is carried out using an elastic network model for the protein, and the solvent motions are described by multiparticle collision dynamics, which incorporates hydrodynamic flow effects. Systems where solvent-enzyme coupling occurs through explicit intermolecular interactions, as well as systems where this coupling is taken into account by including the protein and substrate in the multiparticle collision step, are investigated and compared with simulations where hydrodynamic coupling is absent. It is demonstrated that the flow of solvent particles around the enzyme facilitates the large-scale hinge motion of the enzyme with bound substrates, and has a significant impact on the shape of the probability densities and average time scales of substrate binding for substrates near the enzyme, the closure of the enzyme after binding, and the overall time of completion of the cycle.