Detecting evolutionary relationships across existing fold space, using sequence order-independent profile-profile alignments

Abstract

Here, a scalable, accurate, reliable, and robust protein functional site comparison algorithm is presented. The key components of the algorithm consist of a reduced representation of the protein structure and a sequence order-independent profile-profile alignment (SOIPPA). We show that SOIPPA is able to detect distant evolutionary relationships in cases where both a global sequence and structure relationship remains obscure. Results suggest evolutionary relationships across several previously evolutionary distinct protein structure superfamilies. SOIPPA, along with an increased coverage of protein fold space afforded by the structural genomics initiative, can be used to further test the notion that fold space is continuous rather than discrete.

Fig. 1.

RMSD distribution of the aligned common fragments of ligands from the 247-benchmark, using maximum size clique with amino acid grouping (Amino Acid Grouping), maximum weight common subgraph with chemical similarity (Chemical Similarity), substitution matrix, SOIPPA, and CE.

Fig. 2.

False-positive ratio vs. true-positive ratio for PSI-BLAST, CE, and SOIPPA. The aligned 247-benchmark pair is defined as a true positive if the two proteins are from the same (A) and different (B) SCOP superfamilies.

Fig. 3.

False-positive vs. true-positive ratios, using all 247-benchmark pairs, using maximum size clique with amino acid grouping (Amino Acid Group); maximum weight common subgraph with chemical similarity (Chemical Similarity); and substitution matrix, SOIPPA, and CE.

Fig. 4.

Multiple functional site alignment of a Rossmann NAD-binding protein (PDB ID code 2C5A) with four other proteins having the Rossmann topology but different SCOP superfamilies. The three conserved motifs are marked motif 1–3. The most conserved residues are labeled as red; and partially conserved residues are labeled as blue. Their corresponding SCOP superfamilies are listed in Table 1. The multiple functional site alignment is generated from pairwise SOIPPA alignments.