CAN 3-DIMENSIONAL CONTACTS IN PROTEIN STRUCTURES BE PREDICTED BY ANALYSIS OF CORRELATED MUTATIONS

A method has been developed to detect pairs of positions with correlat ed mutations in protein multiple sequence alignments. The method is ba sed on reconstruction of the phylogenetic tree for a set of sequences and statistical analysis of the distribution of mutations in the branc hes of the tree. The database of homology-derived protein structures ( HSSP) is used as the source of multiple sequence alignments for protei ns of known three-dimensional structure. We analyse pairs of positions with correlated mutations in 67 protein families and show quantitativ ely that the presence of such positions is a typical feature of protei n families. A significant but weak tendency is observed for correlated residue pairs to be close in the three-dimensional structure. With fu rther improvements, methods of this type may be useful for the predict ion of residue-residue contacts and subsequent prediction of protein s tructure using distance geometry algorithms. In conclusion, we suggest a new experimental approach to protein structure determination in whi ch selection of functional mutants after random mutagenesis and analys is of correlated mutations provide sufficient proximity constraints fo r calculation of the protein fold.