Patterns of divergence in homologous proteins as indicators of tertiary and quaternary structure

A new approach for extracting conformational information from an alignment of homologous proteins is presented. This approach extracts information from the pattern of sequence divergence in proteins, and considers evolutionary issues, such as functional adaptation and neutral drift, in assigning roles in tertiary structure to residues at specific positions in the alignment. A reliable algorithm is developed for identifying surface residues in a protein. An algorithm is also developed for identifying active site residues; this algorithm can be applied in cases where functional divergence occurs in one subgroup of homologous proteins but not in others. Finally, these algorithms are used to make predictions regarding the quaternary structure of alcohol dehydrogenase from yeast.