Investigation of rare protein conformational transitions via dissipation-corrected targeted molecular dynamics

TL;DR

This paper explores the use of dissipation-corrected targeted molecular dynamics (dcTMD) to study rare protein conformational transitions and their kinetics, extending its application beyond unbinding events to complex conformational changes.

Contribution

It provides a theoretical framework for applying dcTMD to protein conformational transitions involving multiple collective variables, demonstrating its potential and limitations.

Findings

dcTMD can predict free energy landscapes of protein conformational changes.

The method estimates transition kinetics from dissipated work and friction coefficients.

Application to alanine dipeptide and T4 lysozyme illustrates its effectiveness and challenges.

Abstract

To sample rare events, dissipation-corrected targeted molecular dynamics (dcTMD) applies a constant velocity constraint along a one-dimensional reaction coordinate $s$, which drives an atomistic system from an initial state into a target state. Employing a cumulant approximation of Jarzynski's identity, the free energy $\Delta G (s)$ is calculated from the mean external work and dissipated work of the process. By calculating the friction coefficient $\Gamma (s)$ from the dissipated work, in a second step the equilibrium dynamics of the process can be studied by propagating a Langevin equation. While so far dcTMD has been mostly applied to study the unbinding of protein-ligand complexes, here its applicability to rare conformational transitions within a protein and the prediction of their kinetics is investigated. As this typically requires the introduction of multiple collective variables $\{x_j\}= \vec{x}$, a theoretical framework is outlined to calculate the associated free energy $\Delta G (\vec{x})$ and friction $\matrix{\Gamma}(\vec{x})$ from dcTMD simulations along coordinate $s$. Adopting the $\alpha$-$\beta$ transition of alanine dipeptide as well as the open-closed transition of T4 lysozyme as representative examples, the virtues and shortcomings of dcTMD to predict protein conformational transitions and the related kinetics are studied.