title: Enhancing backbone sampling in Monte Carlo simulations using internal coordinates normal mode analysis.
abstract: Normal mode methods are becoming a popular alternative to sample the conformational landscape of proteins. In this study, we describe the implementation of an internal coordinate normal mode analysis method and its application in exploring protein flexibility by using the Monte Carlo method PELE. This new method alternates two different stages, a perturbation of the backbone through the application of torsional normal modes, and a resampling of the side chains. We have evaluated the new approach using two test systems, ubiquitin and c-Src kinase, and the differences to the original ANM method are assessed by comparing both results to reference molecular dynamics simulations. The results suggest that the sampled phase space in the internal coordinate approach is closer to the molecular dynamics phase space than the one coming from a Cartesian coordinate anisotropic network model. In addition, the new method shows a great speedup (∼5-7×), making it a good candidate for future normal mode implementations in Monte Carlo methods.
authors.affiliation: Joint BSC-CRG-IRB Research Program in Computational Biology, Barcelona Supercomputing Center, 08034 Barcelona, Spain.
authors.forename: Victor A
authors.initials: VA
authors.lastname: Gil
authors.affiliation: Joint BSC-CRG-IRB Research Program in Computational Biology, Barcelona Supercomputing Center, 08034 Barcelona, Spain.
authors.forename: Daniel
authors.initials: D
authors.lastname: Lecina
authors.affiliation: Department of Medicinal Chemistry, CVMD iMed, AstraZeneca, S-43183 Mölndal, Sweden.
authors.forename: Christoph
authors.initials: C
authors.lastname: Grebner
authors.affiliation: Joint BSC-CRG-IRB Research Program in Computational Biology, Barcelona Supercomputing Center, 08034 Barcelona, Spain; Institució Catalana de Recerca i Estudis Avançats (ICREA), Passeig Lluís Companys 23, E-08010 Barcelona, Spain. Electronic address: victor.guallar@bsc.es.
authors.forename: Victor
authors.initials: V
authors.lastname: Guallar
mesh_terms: D000081247:CSK Tyrosine-Protein Kinase; D056004:Molecular Dynamics Simulation; D009010:Monte Carlo Method; D025801:Ubiquitin / Q000737:chemistry*; D019061:src-Family Kinases / Q000737:chemistry* / Q000378:metabolism
chemical_list: D025801:Ubiquitin; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases
keywords: Flexibility sampling; Internal coordinates; Monte Carlo; Normal mode analysis