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.functional site ͉ structure T he evolutionary relationship between protein sequences, protein structures, and their associated function(s) remains a central topic of molecular biology and one resulting in the development of many computational methods (1-3). A central question is: What were the early protein folds and how did these folds change over long evolutionary time scales (4-7)? Comparative genomics studies and structural and phylogenetic analyses (8-10) have established that a subset of proteins, dominated by the structure classification of proteins (SCOP) (11) ␣/␤ class, were likely present in the last universal common ancestor (12, 13). Concurrently, growing evidence suggests that recurring substructures, that is, 3D fragments of noncontiguous sequence shared between different folds, may be clues that protein fold space is more continuous than discreet (14, 15). The sequence/ structure similarity of such substructures correlates well with the similarity of function found between the different folds containing these substructures (16). The notion that protein fold space is a continuum is further supported by recent studies that show that protein domains can adopt different topologies through combination, swapping, deletion (4, 17, 18), and cyclic permutation (19, 20) of subdomains. Likewise, new folds can emerge from accretion (21) or embellishment (22) of substructures around a core of conserved secondary structures. Given these findings concerning the dynamic nature of protein structure and the possible continuous nature of protein fold space, it is important to distinguish proteins that share a common ancestor (divergent evolution) from those that have adopted common structural constraints (convergent evolution).Typically, evolutionary relationships between protein sequence, structure, and function are deduced from the respective comparisons among known genes and their products. These comparisons are made at various levels, from genome sequences to protein domains and motifs to biochemical pathways. Such comparisons may miss important relationships because sequence relationships may be too weak to detect, and/or fail to identify complex evolutionary events such as domain swapping and cyclic permutation. Likewise, differences in global protein structure may disgu...

A galaxy of folds

“…Their evolutionary relationship has also been proposed previously. 14,23 A further cluster comprises the eukaryotic (Type-I) and the prokaryotic (Type-II) KH-domains, which are topologically distinct but homologous. 43 The similarity between these folds is limited to a baab motif.…”

“…It would not appear to be so. In recent years, the dramatic expansion of molecular databases and the development of a new generation of highly sensitive sequence comparison methods [10][11][12][13][14] has revealed a growing number of distant evolutionary relationships, which transcend the previous boundaries between homology and analogy. For instance, most families of the TIM (ba) 8 -barrel fold are now thought to have arisen from a common ancestor.…”

A Systematic Approach to Identifying Protein-Ligand Binding Profiles on a Proteome Scale

“…Moreover, we have discovered that the marketed pharmaceuticals Entacapone (ENT) and Tolcapone (TOL) used for treating Parkinson's disease can potentially be repositioned to treat multi drug and extensively drug resistance tuberculosis (TB). The predication is based on the established evolutionary relationship between human SAM methyltransferases (including COMT) and M. tuberculosis enoyl-ACP reductase (InhA), both Rossmann fold proteins and the latter a major target of TB drugs (2). The inhibition by ENT and TOL of M. tuberculosis growth has been validated by microplate assay (Figure 1).…”

Prediction and experimental validation of enzyme substrate specificity in protein structures

“…Other difficulties that plague annotation transfer between homologs are that individual small molecules may each bind to multiple and distinct molecular pockets (11), that different residues can support similar chemistries (12), and that activity can vary even when catalytic residues are conserved (13)(14)(15)(16)(17)(18). To raise annotation accuracy, Structural Genomics (19) made structural information widely available and spurred the development of annotation methods dependent on local chemical and physical environments (20), sequence and structural comparisons (21), or 3D templates (22). In the case of the latter, these methods search between proteins for local structural similarities over a few signature residues that represent the telltale parts of a functional site, so-called "3D templates" (3,14,18,(22)(23)(24).…”