title: Rapid Characterization of Allosteric Networks with Ensemble Normal Mode Analysis.
abstract: Allosteric regulation is a primary means of controlling protein function. By definition, allostery involves the propagation of structural dynamic changes between distal protein sites that yields a functional change. Gaining improved knowledge of these fundamental mechanisms is important for understanding many biomolecular processes and for guiding protein engineering and drug design efforts. In this work we compare and contrast a range of normal mode analysis (NMA) approaches together with network analysis for the prediction of structural dynamics and allosteric sites. Application to heterotrimeric G proteins, hemoglobin, and caspase 7 indicates that atomistic elastic network models provide improved predictions of experimental allosteric mutation sites. Results for G proteins also display an improved consistency with those derived from more computationally demanding MD simulations. Application of this approach across available experimental structures for a given protein family in a unified manner, that we refer to as ensemble NMA, yields the best overall predictive performance. We propose that this atomistic ensemble NMA approach represents an efficient and powerful tool for guiding the exploration of coupled motions and allosteric mechanisms in cases where multiple structures are available and where MD may prove prohibitively expensive.
authors.affiliation: Department of Computational Medicine and Bioinformatics, University of Michigan , 100 Washtenaw Avenue, 2017 Palmer Commons Building, Ann Arbor, Michigan 48109-2218, United States.
authors.forename: Xin-Qiu
authors.initials: XQ
authors.lastname: Yao
authors.affiliation: Department of Biomedicine, University of Bergen , Bergen N-5020, Norway.
authors.forename: Lars
authors.initials: L
authors.lastname: Skjærven
authors.affiliation: Department of Computational Medicine and Bioinformatics, University of Michigan , 100 Washtenaw Avenue, 2017 Palmer Commons Building, Ann Arbor, Michigan 48109-2218, United States.
authors.forename: Barry J
authors.initials: BJ
authors.lastname: Grant
mesh_terms: D000494:Allosteric Regulation; D000495:Allosteric Site; D053179:Caspase 7 / Q000737:chemistry*; D044385:GTP-Binding Protein alpha Subunits / Q000737:chemistry* / Q000235:genetics; D006153:Guanosine Diphosphate / Q000737:chemistry*; D006160:Guanosine Triphosphate / Q000737:chemistry*; D006454:Hemoglobins / Q000737:chemistry*; D006801:Humans; D056004:Molecular Dynamics Simulation; D009154:Mutation; D011485:Protein Binding; D000072756:Protein Conformation, alpha-Helical; D000072757:Protein Conformation, beta-Strand; D054730:Protein Interaction Domains and Motifs; D013816:Thermodynamics
chemical_list: D044385:GTP-Binding Protein alpha Subunits; D006454:Hemoglobins; D006153:Guanosine Diphosphate; D006160:Guanosine Triphosphate; C505520:CASP7 protein, human; D053179:Caspase 7