multiscale coarse-graining of the protein energy landscape多尺度的粗粒度的蛋白质能源格局.pdfVIP

Multiscale Coarse-Graining of the Protein Energy Landscape Ronald D. Hills Jr.1,2, Lanyuan Lu1,2, Gregory A. Voth1,2* 1 Department of Chemistry, James Franck Institute and Computation Institute, University of Chicago, Chicago, Illinois, United States of America, 2 Department of Chemistry and Center for Biophysical Modeling and Simulation, University of Utah, Salt Lake City, Utah, United States of America Abstract A variety of coarse-grained (CG) models exists for simulation of proteins. An outstanding problem is the construction of a CG model with physically accurate conformational energetics rivaling all-atom force fields. In the present work, atomistic simulations of peptide folding and aggregation equilibria are force-matched using multiscale coarse-graining to develop and test a CG interaction potential of general utility for the simulation of proteins of arbitrary sequence. The reduced representation relies on multiple interaction sites to maintain the anisotropic packing and polarity of individual sidechains. CG energy landscapes computed from replica exchange simulations of the folding of Trpzip, Trp-cage and adenylate kinase resemble those of other reduced representations; non-native structures are observed with energies similar to those of the native state. The artifactual stabilization of misfolded states implies that non-native interactions play a deciding role in deviations from ideal funnel-like cooperative folding. The role of surface tension, backbone hydrogen bonding and the smooth pairwise CG landscape is discussed. Ab initio folding aside, the improved treatment of sidechain rotamers results in stability of the native state in constant temperature simulations of Trpzip, Trp-cage, and the open to closed conformational transition of adenyla