2023/09/15 by Matthias Post, Post, Matthias, Steffen Wolf +3
Biochemistry, Genetics and Molecular Biology · Physics and Astronomy · #Biological Physics (physics.bio-ph) #Biomolecules (q-bio.BM) #DNA and Nucleic Acid Chemistry #FOS: Biological sciences #FOS: Physical sciences #Protein Structure and Dynamics #Spectroscopy and Quantum Chemical Studies #Statistical Mechanics (cond-mat.stat-mech)
paper · pdf · doi:10.48550/arxiv.2309.08759
openalex publication_date 2023/09/15 · openalex created_date 2023/09/20 · openalex updated_date 2026/07/28
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 ΔG (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 is investigated. As this typically requires the introduction of multiple collective variables \xj\= x, a theoretical framework is outlined to calculate the associated free energy ΔG (x) and friction \matrixΓ(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.