Protein backbone angle restraints from searching a database for chemical shift and sequence homology

Chemical shifts of backbone atoms in proteins are exquisitely sensitive to local conformation, and homologous proteins show quite similar patterns of secondary chemical shifts. The inverse of this relation is used to search a database for triplets of adjacent residues with secondary chemical shifts and sequence similarity which provide the best match to the query triplet o f interest. The database contains C-13(alpha), C-13(beta), C-13', H-1(alpha ) and N-15 chemical shifts for 20 proteins for which a high resolution X-ra y structure is available. The computer program TALOS was developed to searc h this database for strings of residues with chemical shift and residue typ e homology. The relative importance of the weighting factors attached to th e secondary chemical shifts of the five types of resonances relative to tha t of sequence similarity was optimized empirically. TALOS yields the 10 tri plets which have the closest similarity in secondary chemical shift and ami no acid sequence to those of the query sequence. If the central residues in these 10 triplets exhibit similar phi and Psi backbone angles, their avera ges can reliably be used as angular restraints for the protein whose struct ure is being studied. Tests carried out for proteins of known structure ind icate that the root-mean-square difference (rmsd) between the output of TAL OS and the X-ray derived backbone angles is about 15 degrees. Approximately 3% of the predictions made by TALOS are found to be in error.