Statistical and visual morph movie analysis of crystallographic mutant selection bias in protein mutation resource data.
Structural studies of the effects of non-silent mutations on protein conformational change are an important key in deciphering the language that relates protein amino acid primary structure to tertiary structure. Elsewhere, we presented the Protein Mutant Resource (PMR) database, a set of online tools that systematically identified groups of related mutant structures in the Protein DataBank (PDB), accurately inferred mutant classifications in the Gene Ontology using an innovative, statistically rigorous data-mining algorithm with more general applicability, and illustrated the relationship of these mutant structures via an intuitive user interface. Here, we perform a comprehensive statistical analysis of the effect of PMR mutations on protein tertiary structure. We find that, although the PMR does contain spectacular examples of conformational change, in general there is a counter-intuitive inverse relationship between conformational change (measured as C-alpha displacement or RMS of the core structure) and the number of mutations in a structure. That is, point mutations by structural biologists present in the PDB contrast naturally evolved mutations. We compare the frequency of mutations in the PMR/PDB datasets against the accepted PAM250 natural amino acid mutation frequency to confirm these observations. We generated morph movies from PMR structure pairs using technology previously developed for the Macromolecular Motions Database (http://molmovdb.org), allowing bioinformaticians, geneticists, protein engineers, and rational drug designers to analyze visually the mechanisms of protein conformational change and distinguish between conformational change due to motions (e.g., ligand binding) and mutations. The PMR morph movies and statistics can be freely viewed from the PMR website, http://pmr.sdsc.edu.
Krebs
Werner G
WG
Department of Pharmacology, Integrative Biosciences, San Diego Supercomputer Center Dept 0505, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0505, USA. wkrebs@sdsc.edu
Bourne
Philip E
PE
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D015982:Bias; D003198:Computer Simulation; D003461:Crystallography / Q000379:methods*; D030562:Databases, Protein; D008956:Models, Chemical; D008958:Models, Molecular; D015233:Models, Statistical; D008969:Molecular Sequence Data; D009154:Mutation; D011487:Protein Conformation; D011506:Proteins / Q000737:chemistry* / Q000235:genetics; D016415:Sequence Alignment / Q000379:methods*; D020539:Sequence Analysis, Protein / Q000379:methods*; D014584:User-Computer Interface
D011506:Proteins