Local protein sequence similarity does not imply a structural relationship

Abstract

A database search often will find a seemingly strong sequence similarity between two fragments of proteins that are not expected to have an evolutionary or functional relationship. It is tempting to suggest that the two fragments will adopt a similar conformation due to a common pattern of residues that dictate a particular substructure. To investigate the likelihood of such a structural similarity, local sequence similarities between proteins of known conformation were identified by a standard database search algorithm. Significant sequence similarity was identified as when the chance probability of obtaining the relatedness score from a scan of the entire database was less than 1%. In this region both true homologies and false homologies are detected. A total of 69 false homologies was located of length between 20 and 262 aligned positions. Many of these alignments had approximately 25% sequence identity and a further 25% of conservative changes. However, the results show in general these aligned fragments did not have a significant similarity in secondary or tertiary structure. Thus local sequence does not indicate a structural similarity when there is neither an evolutionary nor functional explanation to support this. Accordingly structure predictions based on finding a local sequence similarity with an evolutionary unrelated protein of known conformation are unlikely to be valid.