title: Can three-dimensional contacts in protein structures be predicted by analysis of correlated mutations?
abstract: A method has been developed to detect pairs of positions with correlated mutations in protein multiple sequence alignments. The method is based on reconstruction of the phylogenetic tree for a set of sequences and statistical analysis of the distribution of mutations in the branches of the tree. The database of homology-derived protein structures (HSSP) is used as the source of multiple sequence alignments for proteins of known three-dimensional structure. We analyse pairs of positions with correlated mutations in 67 protein families and show quantitatively that the presence of such positions is a typical feature of protein families. A significant but weak tendency is observed for correlated residue pairs to be close in the three-dimensional structure. With further improvements, methods of this type may be useful for the prediction of residue--residue contacts and subsequent prediction of protein structure using distance geometry algorithms. In conclusion, we suggest a new experimental approach to protein structure determination in which selection of functional mutants after random mutagenesis and analysis of correlated mutations provide sufficient proximity constraints for calculation of the protein fold.
authors.affiliation: Institute of Cytology and Genetics, Russian Academy of Sciences, Siberian Department, Novosibirsk.
authors.forename: I N
authors.initials: IN
authors.lastname: Shindyalov
authors.forename: N A
authors.initials: NA
authors.lastname: Kolchanov
authors.forename: C
authors.initials: C
authors.lastname: Sander
mesh_terms: D000595:Amino Acid Sequence; D000596:Amino Acids / Q000737:chemistry; D005075:Biological Evolution; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D003574:Cytochrome c Group / Q000737:chemistry; D004268:DNA-Binding Proteins; D008969:Molecular Sequence Data; D015394:Molecular Structure; D016296:Mutagenesis; D009154:Mutation; D017433:Protein Structure, Secondary; D011506:Proteins / Q000737:chemistry*; D012097:Repressor Proteins / Q000737:chemistry; D016415:Sequence Alignment; D014357:Trypsin / Q000737:chemistry; D014764:Viral Proteins; D054334:Viral Regulatory and Accessory Proteins
chemical_list: D000596:Amino Acids; D003574:Cytochrome c Group; D004268:DNA-Binding Proteins; D011506:Proteins; D012097:Repressor Proteins; D014764:Viral Proteins; D054334:Viral Regulatory and Accessory Proteins; C016649:phage repressor proteins; D014357:Trypsin