Molecular dynamics-decorated finite element method (MDeFEM): Application to the gating mechanism of mechanosensitive channels

Many fundamentally important biological processes rely on the mechanical responses of membrane proteins and their assemblies in the membrane environment, which are multiscale in nature and represent a significant challenge in modeling and simulation. For example, in mechanotransduction, mechanical stimuli can be introduced through macroscopic-scale contacts, which are transduced to mesoscopic-scale (micron) distances and can eventually lead to microscopicscale (nanometer) conformational changes in membrane-bound protein or protein complexes. This is a fascinating process that spans a large range of length scales and time scales. The involvement of membrane environment and critical issues such as cooperativity calls for the need for an efficient multi-scale computational approach. The goal of the present research is to develop a hierarchical approach to study the mechanical behaviors of membrane proteins with a special emphasis on the gating mechanisms of mechanosensitive (MS) channels. This requires the formulation of modeling and numerical methods that can effectively bridge the disparate length and time scales. A top-down approach is proposed to achieve this by effectively treating biomolecules and their assemblies as integrated structures, in which the most important components of the biomolecule (e.g., MS channel) are modeled as continuum objects, yet their mechanical/physical properties, as well as their interactions, are derived from atomistic simulations. Molecular dynamics (MD) simulations at the nanoscale are used to obtain information on the physical properties and interactions among protein, lipid membrane, and solvent molecules, as well as relevant energetic and temporal characteristics. Effective continuum models are developed to incorporate these atomistic features, and the conformational response of macromolecule(s) to external mechanical perturbations is simulated using finite element (FEM) analyses with in situ mechanochemical coupling. Results from the continuum mechanics analysis provide further insights into the gating transition of MS channels at structural and physical levels, and specific predictions are proposed for further experimental investigations. It is anticipated that the hierarchical framework is uniquely suited for the analysis of many biomolecules and their assemblies under external mechanical stimuli. © Springer Nature Switzerland AG 2019. All rights reserved.