title: Modeling Structural Flexibility of Proteins with Go-Models.
abstract: Structure-based models are an efficient tool for folding studies of proteins since by construction their energy landscape is only minimal frustrated. However, their intrinsic drawback is a lack of structural flexibility as usually only one target structure is employed to construct the potentials. Hence, a Go-model may not capture differences in mutation-induced protein dynamics, if - as in the case of the disease-related A629P mutant of the Menkes protein ATP7A - the structural differences between mutant and wild type are small. In this work, we introduced three implementations of Go-models that take into account the flexibility of proteins in the NMR ensemble. Comparing the wild type and the mutant A629P of the 75-residue large 6th domain Menkes protein, we find that these new Go-potentials lead to broader distributions than Go-models relying on a single member of the NMR-ensemble. This allows us to detect the transient unfolding of a loosely formedβ1β4-sheet in the mutant protein. Our results are consistent with previous simulations using physical force field and an explicit solvent, and suggests a mechanism by which these mutations cause Menkes disease. In addition, the improved Go-models suggest differences in the folding pathway between wild type and mutant, an observation that was not accessible to simulations of this 75-residue protein with a physical all-atom force field and explicit solvent.
authors.affiliation: Department of Chemistry and Biochemistry, University of Oklahoma, Norman, OK 73019-5251, USA.
authors.forename: Ping
authors.initials: P
authors.lastname: Jiang
authors.forename: Ulrich H E
authors.initials: UH
authors.lastname: Hansmann
references.citation: Biophys J. 2006 Nov 15;91(10):3573-8
references.pmid: 16950845
references.citation: Proteins. 2009 May 1;75(2):430-41
references.pmid: 18837035
references.citation: Nucleic Acids Res. 2010 Jul;38(Web Server issue):W657-61
references.pmid: 20525782
references.citation: Phys Rev E Stat Nonlin Soft Matter Phys. 2007 Feb;75(2 Pt 2):026109
references.pmid: 17358396
references.citation: Curr Opin Struct Biol. 2005 Apr;15(2):144-50
references.pmid: 15837171
references.citation: Biopolymers. 1983 Dec;22(12):2577-637
references.pmid: 6667333
references.citation: Structure. 2005 Dec;13(12):1755-63
references.pmid: 16338404
references.citation: Proc Natl Acad Sci U S A. 2009 Jul 21;106(29):11823-4
references.pmid: 19617547
references.citation: Proc Natl Acad Sci U S A. 2006 Aug 8;103(32):11844-9
references.pmid: 16877541
references.citation: Nature. 2003 Dec 18;426(6968):900-4
references.pmid: 14685251
references.citation: J Chem Theory Comput. 2008 Mar;4(3):435-47
references.pmid: 26620784
references.citation: Proteins. 2006 Apr 1;63(1):165-73
references.pmid: 16416404
references.citation: Nat Phys. 2010 Oct 1;6(10):751-758
references.pmid: 21297873
references.citation: Phys Chem Chem Phys. 2010 Oct 7;12(37):11390-7
references.pmid: 20714486
references.citation: Proteins. 2009 Dec;77(4):881-91
references.pmid: 19626713
references.citation: PLoS Comput Biol. 2008 Apr 11;4(4):e1000060
references.pmid: 18404207
references.citation: Proc Natl Acad Sci U S A. 1999 Oct 26;96(22):12512-7
references.pmid: 10535953
references.citation: Biochim Biophys Acta. 2008 Jan;1784(1):252-8
references.pmid: 18036571
references.citation: Nat Genet. 1993 Jan;3(1):7-13
references.pmid: 8490659
references.citation: Proc Natl Acad Sci U S A. 1993 Mar 1;90(5):1942-6
references.pmid: 7680482