Free-energy landscapes of transmembrane homodimers by bias-exchange adaptively biased molecular dynamics

GENESIS 2.1: High-Performance Molecular Dynamics Software for Enhanced Sampling and Free-Energy Calculations for Atomistic, Coarse-Grained, and Quantum Mechanics/Molecular Mechanics Models

“…Besides the necessity of the convergence of bias potential and the time-dependent reweighting after the simulations, ABMD and their variants, bias-exchange ABMD (BE-ABMD), multiwalker ABMD, and so on, can be used for MD simulations of large biomolecules without using many replicas. We have recently implemented ABMD and BE-ABMD into the developer’s version of GENESIS . Using the BE-ABMD method, dimerization processes of two single-transmembrane helices, such as Glycophorin A (GpA) and amyloid precursor protein (APP), can be predicted with their free-energy landscapes, demonstrating the superior performance compared to the multidimensional REUS.…”

“…We have recently implemented ABMD and BE-ABMD into the developer’s version of GENESIS. 175 Using the BE-ABMD method, dimerization processes of two single-transmembrane helices, such as Glycophorin A (GpA) and amyloid precursor protein (APP), can be predicted with their free-energy landscapes, demonstrating the superior performance compared to the multidimensional REUS. Since ABMD or BE-ABMD requires CVs that are useful for efficient conformational sampling of target problems, we need to add more flexible definitions of CVs in MD simulations with GENESIS (In the current version of GENESIS, we use distance, angle, dihedral angle, position coordinates, principal component, and root-mean-squared deviation from reference as CVs).…”

Machine Learning Derived Collective Variables for the Study of Protein Homodimerization in Membrane

“…Most membrane proteins contain one or more transmembrane (TM) regions that span the membrane bilayer. , Membrane proteins also play crucial roles in cellular signaling with G-protein coupled receptors representing common therapeutic targets . Association of membrane associated enzymes and their substrates through the interaction of the TM domains is known to play a key role in the biogenesis of a diverse array of proteins including the amyloid-β (Aβ) protein in Alzheimer’s disease. , As a result, the association of TM regions of the protein in membrane has received significant attention in experiment, theory, and simulations for over four decades. − Nevertheless, there remain fundamental outstanding questions related to the nature of the associated state and the magnitude of related equilibrium association constants.…”