title: All-atom and coarse-grained molecular dynamics simulations of a membrane protein stabilizing polymer.
abstract: Amphipathic polymers called amphipols (APols) have been developed as an alternative to detergents for stabilizing membrane proteins (MPs) in aqueous solutions. APols provide MPs with a particularly mild environment and, as a rule, keep them in a native functional state for longer periods than do detergents. Amphipol A8-35, a derivative of polyacrylate, is widely used and has been particularly well studied experimentally. In aqueous solutions, A8-35 molecules self-assemble into well-defined globular particles with a mass of ∼40 kDa and a R(g) of ∼2.4 nm. As a first step towards describing MP/A8-35 complexes by molecular dynamics (MD), we present three sets of simulations of the pure APol particle. First, we performed a series of all-atom MD (AAMD) simulations of the particle in solution, starting from an arbitrary initial configuration. Although AAMD simulations result in stable cohesive particles over a 45 ns simulation, the equilibration of the particle organization is limited. This motivated the use of coarse-grained MD (CGMD), allowing us to investigate processes on the microsecond time scale, including de novo particle assembly. We present a detailed description of the parametrization of the CGMD model from the AAMD simulations and a characterization of the resulting CGMD particles. Our third set of simulations utilizes reverse coarse-graining (rCG), through which we obtain all-atom coordinates from a CGMD simulation. This allows a higher-resolution characterization of a configuration determined by a long-timescale simulation. Excellent agreement is observed between MD models and experimental, small-angle neutron scattering data. The MD data provides new insight into the structure and dynamics of A8-35 particles, which is possibly relevant to the stabilizing effects of APols on MPs, as well as a starting point for modeling MP/A8-35 complexes.
authors.affiliation: Department of Biomedical Engineering, 312 Church Street SE, University of Minnesota, Minneapolis, Minnesota 55455, USA.
authors.forename: Jason D
authors.initials: JD
authors.lastname: Perlmutter
authors.forename: William J
authors.initials: WJ
authors.lastname: Drasler
authors.forename: Wangshen
authors.initials: W
authors.lastname: Xie
authors.forename: Jiali
authors.initials: J
authors.lastname: Gao
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Popot
authors.forename: Jonathan N
authors.initials: JN
authors.lastname: Sachs
mesh_terms: D000180:Acrylic Resins / Q000737:chemistry*; D008565:Membrane Proteins / Q000737:chemistry*; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation
chemical_list: D000180:Acrylic Resins; D008565:Membrane Proteins