title: Computation of conformational transitions in proteins by virtual atom molecular mechanics as validated in application to adenylate kinase.
abstract: Many proteins function through conformational transitions between structurally disparate states, and there is a need to explore transition pathways between experimentally accessible states by computation. The sizes of systems of interest and the scale of conformational changes are often beyond the scope of full atomic models, but appropriate coarse-grained approaches can capture significant features. We have designed a comprehensive knowledge-based potential function based on a C alpha representation for proteins that we call the virtual atom molecular mechanics (VAMM) force field. Here, we describe an algorithm for using the VAMM potential to describe conformational transitions, and we validate this algorithm in application to a transition between open and closed states of adenylate kinase (ADK). The VAMM algorithm computes normal modes for each state and iteratively moves each structure toward the other through a series of intermediates. The move from each side at each step is taken along that normal mode showing greatest engagement with the other state. The process continues to convergence of terminal intermediates to within a defined limit--here, a root-mean-square deviation of 1 A. Validations show that the VAMM algorithm is highly effective, and the transition pathways examined for ADK are compatible with other structural and biophysical information. We expect that the VAMM algorithm can address many biological systems.
authors.affiliation: Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032, USA.
authors.forename: Anil
authors.initials: A
authors.lastname: Korkut
authors.forename: Wayne A
authors.initials: WA
authors.lastname: Hendrickson
mesh_terms: D000263:Adenylate Kinase / Q000737:chemistry*; D000465:Algorithms; D055592:Biophysical Phenomena; D018360:Crystallography, X-Ray; D008958:Models, Molecular; D011487:Protein Conformation; D013816:Thermodynamics; D014584:User-Computer Interface
chemical_list: D000263:Adenylate Kinase
references.citation: Proc Natl Acad Sci U S A. 1983 Nov;80(21):6571-5
references.pmid: 6579545
references.citation: Curr Opin Struct Biol. 2003 Dec;13(6):748-57
references.pmid: 14675554
references.citation: Biophys J. 2001 Jan;80(1):505-15
references.pmid: 11159421
references.citation: Proc Natl Acad Sci U S A. 2009 Sep 15;106(37):15667-72
references.pmid: 19717427
references.citation: Nucleic Acids Res. 2007 Jul;35(Web Server issue):W375-83
references.pmid: 17452350
references.citation: Curr Opin Struct Biol. 2007 Dec;17(6):633-40
references.pmid: 18024008
references.citation: Curr Opin Struct Biol. 2005 Oct;15(5):586-92
references.pmid: 16143512
references.citation: Biopolymers. 1983 Dec;22(12):2577-637
references.pmid: 6667333
references.citation: Proteins. 1997 Nov;29(3):292-308
references.pmid: 9365985
references.citation: J Mol Biol. 1996 Feb 23;256(2):223-7
references.pmid: 8594191
references.citation: Nature. 2007 Dec 6;450(7171):838-44
references.pmid: 18026086
references.citation: Structure. 2008 Aug 6;16(8):1175-82
references.pmid: 18682219
references.citation: Bioinformatics. 2001 Dec;17(12):1242-3
references.pmid: 11751240
references.citation: Proc Natl Acad Sci U S A. 2007 Nov 20;104(47):18496-501
references.pmid: 18000050
references.citation: J Mol Biol. 2005 Sep 30;352(4):807-22
references.pmid: 16139299
references.citation: J Mol Biol. 2007 Mar 9;366(5):1661-71
references.pmid: 17217965
references.citation: Proteins. 2003 Feb 15;50(3):437-50
references.pmid: 12557186
references.citation: Proteins. 2008 Jan 1;70(1):131-43
references.pmid: 17640073
references.citation: Biochemistry. 1994 Jun 7;33(22):6739-49
references.pmid: 8204609
references.citation: Proc Natl Acad Sci U S A. 1998 Jul 21;95(15):8502-7
references.pmid: 9671707
references.citation: Proteins. 1995 Dec;23(4):557-60
references.pmid: 8749851
references.citation: J Mol Biol. 1985 Feb 5;181(3):423-47
references.pmid: 2580101
references.citation: Proteins. 2007 May 1;67(2):325-37
references.pmid: 17299745
references.citation: Nature. 2007 Dec 6;450(7171):913-6
references.pmid: 18026087
references.citation: Nature. 2005 Nov 3;438(7064):117-21
references.pmid: 16267559
references.citation: Proc Natl Acad Sci U S A. 2007 Nov 13;104(46):18055-60
references.pmid: 17989222
references.citation: Biochimie. 1998 Jan;80(1):33-42
references.pmid: 9587660
references.citation: Structure. 1996 Feb 15;4(2):147-56
references.pmid: 8805521
references.citation: Proteins. 2007 Oct 1;69(1):43-57
references.pmid: 17596847
references.citation: Science. 2008 Jun 13;320(5882):1471-5
references.pmid: 18556554
references.citation: Protein Sci. 1996 Mar;5(3):434-41
references.pmid: 8868479
references.citation: Structure. 1995 May 15;3(5):483-90
references.pmid: 7663945
references.citation: Chem Rev. 2006 May;106(5):1589-615
references.pmid: 16683746
references.citation: J Mol Biol. 1991 Feb 5;217(3):541-9
references.pmid: 1994037
references.citation: J Mol Biol. 1997 Nov 21;274(1):114-31
references.pmid: 9398520