Multi-Scale Molecular Dynamics Simulations of a Membrane Protein Stabilizing Polymer

Abstract

Amphipathic polymers have been developed as an alternative to detergents for the stabilization of membrane proteins during structural characterization. These polymers have been demonstrated to provide a less dissociative environment than detergents, and are thus able to sustain the native, oligomeric state of membrane proteins. The most successful polymer, A8-35, consists of a hydrophilic polyacrylate backbone with hydrophobic octylamine groups covalently attached. In order to better understand the mechanism by which these A8-35 polymers bind and stabilize membrane proteins, we present two sets of simulations. First, we present a series of all-atom molecular dynamics (AAMD) simulations of the amphipol particle in solution. Experimental studies have shown that the polymer forms cohesive particles consisting of four chains. While our AAMD simulations result in cohesive and stable particles over a 45 ns simulation, and whose structure is in agreement with small angle neutron scattering, the equilibration of the particle structure is limited in AAMD. Therefore, we present a second series of simulations using coarse-grained molecular dynamics (CGMD). This includes parameterization of the bonded and non-bonded terms in the Martini force field, and comparison of the particles formed by microsecond-scale CGMD with the particles formed by AAMD. Finally, we present initial simulations of the amphipol polymer interaction with lipid bilayers and membrane proteins.