Identification of homologous core structures

Using a large database of protein structure-structure alignments, we test a new method for distinguishing homologous and "analogous" structural neighb ors. The homologous neighbors included in the test set show no detectable s equence similarity but they may be well superimposed and show functional si milarity or other evidence of evolutionary relationship. Analogous neighbor s also show no sequence similarity and may be well superimposed, but they h ave different functions and their structural similarity may be the result o f convergent evolution. Confirming results of other analyses, we find that remote homologs and analogs are not well distinguished by measures of pairw ise structural similarity including the percentage of identical residues an d root-mean-square (RMS) superposition residual. We show, however, that wit h structure-structure alignments of analogous neighbors rarely superimpose the particular substructure that is shared among homologous neighbors. We c all this characteristic substructure the homologous core structure (HCS), a nd we show that a cross-validated test for presence of the HCS correctly id entifies 75% of remote homologs with a false-positive rate of 16% analogs, significantly better than discrimination by RMS or other measures of pairwi se similarity The HCS describes conservation of spatial structure within a protein family in much the way that a sequence motif describes sequence con servation. We suggest that it may be used in the same way, to identify homo logous neighbors at greater evolutionary distance than is possible by pairw ise comparison. Proteins 1999;35:70-79. Published 1999 Wiley-Liss, Inc.