On the use of sequence homologies Identical pentapeptides can have cc (cooperativity/protein folding/amino acid sequence homology)

The search for amino acid sequence homolo- gies can be a powerful tool for predicting protein structure. Discovered sequence homologies are currently used in predict- ing the function of oncogene proteins. To sharpen this tool, we investigated the structural significance of short sequence ho- mologies by searching proteins of known three-dimensional structure for subsequence identities. In 62 proteins with 10,000 residues, we found that the longest isolated homologies between unrelated proteins are five residues long. In 6 (out of 25) cases we saw surprising structural adaptability: the same five residues are part of an a-helix in one protein and part of a ,B-strand in another protein. These examples show quantita- tively that pentapeptide structure within a protein is strongly dependent on sequence context, a fact essentially ignored in most protein structure prediction methods: just considering the local sequence of five residues is not sufficient to predict correctly the local conformation (secondary structure). Coop- erativity of length six or longer must be taken into account. Also, we are warned that in the growing practice of comparing a new protein sequence with a data base of known sequences, finding an identical pentapeptide sequence between two pro- teins is not a significant indication of structural similarity or of evolutionary kinship.