Sensitive methods for determining the relatedness of proteins with limited sequence homology

Recently, considerable advances have been made in attempts to determine the relatedness of protein sequences distant in evolution, when little or no knowledge is available concerning the corresponding tertiary architectures. Several improvements have been made to existing techniques, and these include better amino acid substitution weights contained in scoring matrices, better understanding of the effect of different gap penalty values in delineating the optimal alignment of two sequences, improved assessment of the significance of suggested sequence similarities, consideration of high scoring alternative alignments, and advances in searching entire sequence databases with the profile technique utilizing multiple-sequence information. New approaches that search for similarity a query sequence against large data banks rely on highly conserved segmental motifs defined from an aligned family of sequences. A sensitive algorithm to find distant repeats within one primary structure has also been developed recently. Solution of the inverse protein-folding problem, which involves an estimation of the ability of a sequence to take on a known main-chain tertiary topology (despite little homology with the known sequence), is being facilitated by the recent explosion in the number of new algorithms.