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Gating Mechanisms of Mechanosensitive Channels of Large Conductance, I: A Continuum Mechanics-Based Hierarchical Framework

Xi Chen ^*, Qiang Cui , Yuye Tang ^*, Jejoong Yoo  and Arun Yethiraj 

^* Nanomechanics Research Center, Department of Civil Engineering and Engineering Mechanics, Columbia University, New York, New York 10027; and Theoretical Chemistry Institute, Department of Chemistry, University of Wisconsin, Madison, Wisconsin 53706

Correspondence: Address reprint requests to Xi Chen, Tel.: 212-854-3787; Fax: 212-854-6267; E-mail: xichen{at}civil.columbia.edu.

A hierarchical simulation framework that integrates information from molecular dynamics (MD) simulations into a continuum model is established to study the mechanical response of mechanosensitive channel of large-conductance (MscL) using the finite element method (FEM). The proposed MD-decorated FEM (MDeFEM) approach is used to explore the detailed gating mechanisms of the MscL in Escherichia coli embedded in a palmitoyloleoylphosphatidylethanolamine lipid bilayer. In Part I of this study, the framework of MDeFEM is established. The transmembrane and cytoplasmic helices are taken to be elastic rods, the loops are modeled as springs, and the lipid bilayer is approximated by a three-layer sheet. The mechanical properties of the continuum components, as well as their interactions, are derived from molecular simulations based on atomic force fields. In addition, analytical closed-form continuum model and elastic network model are established to complement the MDeFEM approach and to capture the most essential features of gating. In Part II of this study, the detailed gating mechanisms of E. coli-MscL under various types of loading are presented and compared with experiments, structural model, and all-atom simulations, as well as the analytical models established in Part I. It is envisioned that such a hierarchical multiscale framework will find great value in the study of a variety of biological processes involving complex mechanical deformations such as muscle contraction and mechanotransduction.