Investigation of Rare Protein Conformational Transitions via Dissipation-Corrected Targeted Molecular Dynamics.

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 Δ G ( s ) is calculated from the mean external work and dissipated work of the process. By calculating the friction coefficient Γ( 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 are investigated. As this typically requires the introduction of multiple collective variables { x j } = x , a theoretical framework is outlined to calculate the associated free energy Δ G ( x ) and friction Γ ( x ) from dcTMD simulations along coordinate s . Adopting the α-β 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.