title: Finite Temperature String Method with Umbrella Sampling: Application on a Side Chain Flipping in Mhp1 Transporter.
abstract: Protein conformational change is of central importance in molecular biology. Here we demonstrate a computational approach to characterize the transition between two metastable conformations in all-atom simulations. Our approach is based on the finite temperature string method, and the implementation is essentially a generalization of umbrella sampling simulations with Hamiltonian replica exchange. We represent the transition pathway by a curve in the conformational space, with the curve parameter taken as the reaction coordinate. Our approach can efficiently refine a transition pathway and compute a one-dimensional free energy as a function of the reaction coordinate. A diffusion model can then be used to calculate the forward and backward transition rates, the major kinetic quantities for the transition. We applied the approach on a local transition in the ligand-free Mhp1 transporter, between its outward-facing conformation and an intermediate conformation with the side chain of Phe305 flipped to the outside of the protein. Our simulations predict that the flipped-out position of this side chain has a free energy 6.5 kcal/mol higher than the original position in the crystal structure, and that the forward and backward transition rates are in the millisecond and submicrosecond time scales, respectively.
authors.affiliation: Department of Physics, Indiana University - Purdue University Indianapolis , Indianapolis, Indiana 46202, United States.
authors.forename: Hyun Deok
authors.initials: HD
authors.lastname: Song
authors.affiliation: Department of Physics, Indiana University - Purdue University Indianapolis , Indianapolis, Indiana 46202, United States.
authors.forename: Fangqiang
authors.identifier: 0000-0001-6202-2262
authors.initials: F
authors.lastname: Zhu
mesh_terms: D039903:Actinobacteria / Q000737:chemistry; D001426:Bacterial Proteins / Q000737:chemistry*; D004058:Diffusion; D056004:Molecular Dynamics Simulation; D011487:Protein Conformation; D013696:Temperature; D013816:Thermodynamics
chemical_list: D001426:Bacterial Proteins