title: Using enhanced sampling and structural restraints to refine atomic structures into low-resolution electron microscopy maps.
abstract: For a variety of problems in structural biology, low-resolution maps generated by electron microscopy imaging are often interpreted with the help of various flexible-fitting computational algorithms. In this work, we systematically analyze the quality of final models of various proteins obtained via molecular dynamics flexible fitting (MDFF) by varying the map-resolution, strength of structural restraints, and the steering forces. We find that MDFF can be extended to understand conformational changes in lower-resolution maps if larger structural restraints and lower steering forces are used to prevent overfitting. We further show that the capabilities of MDFF can be extended by combining it with an enhanced conformational sampling method, temperature-accelerated molecular dynamics (TAMD). Specifically, either TAMD can be used to generate better starting configurations for MDFF fitting or TAMD-assisted MDFF (TAMDFF) can be performed to accelerate conformational search in atomistic simulations.
authors.affiliation: Department of Chemistry and Biophysics Program, University of Michigan, 930 North University Avenue, Chem 2006, Ann Arbor, MI 48109, USA. harishv@umich.edu
authors.forename: Harish
authors.initials: H
authors.lastname: Vashisth
authors.forename: Georgios
authors.initials: G
authors.lastname: Skiniotis
authors.forename: Charles L
authors.initials: CL
authors.lastname: Brooks
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000737:chemistry; D000263:Adenylate Kinase / Q000737:chemistry; D018834:Chaperonin 60 / Q000737:chemistry; D058619:Maltose-Binding Proteins / Q000737:chemistry; D008854:Microscopy, Electron; D056004:Molecular Dynamics Simulation; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D021122:Protein Subunits / Q000737:chemistry; D012997:Solvents
chemical_list: D018528:ATP-Binding Cassette Transporters; D018834:Chaperonin 60; D058619:Maltose-Binding Proteins; D021122:Protein Subunits; D012997:Solvents; D000263:Adenylate Kinase