Combining specificity determining and conserved residues improves functional site prediction

Abstract

Background: Predicting the location of functionally important sites from protein sequence and/ or structure is a long-standing problem in computational biology. Most current approaches make use of sequence conservation, assuming that amino acid residues conserved within a protein family are most likely to be functionally important. Most often these approaches do not consider many residues that act to define specific sub-functions within a family, or they make no distinction between residues important for function and those more relevant for maintaining structure (e.g. in the hydrophobic core). Many protein families bind and/or act on a variety of ligands, meaning that conserved residues often only bind a common ligand sub-structure or perform general catalytic activities.

pocketZebra: a web-server for automated selection and classification of subfamily-specific binding sites by bioinformatic analysis of diverse protein families

“…It was shown that enzyme active centers contain significant amount of both conserved and subfamily-specific positions (19,23,24). However, the catalytic sites are not the sole determinants of a protein function as binding of biologically active compounds to other parts of the structure can have significant impact on function and regulation.…”

Molecular dynamics and docking simulations as a proof of high flexibility in E. coli FabH and its relevance for accurate inhibitor modeling

“…This inter-species extrapolation of the binding mode of ligands from one protein to a highly conserved one in a different species is often used in the context of homology modeling, and can be directly corroborated by analyzing the X-ray structure of homologous proteins in complex with the same ligand [68][69][70]. When the alignment of the residues in the binding pocket in ecFabH and efFabH is analyzed, we find that most residues are conserved or mutated by analogous residues (i.e.…”

Homology-Modelling Protein–Ligand Interactions: Allowing for Ligand-Induced Conformational Change

“…This hypothesis includes the notion that highly conserved residues bind common ligand parts and different residues bind different ligand parts. 9,12 As such, different binding-site residues are responsible for different ligand-binding specificities in protein homologues. Using this overall premise, we have constructed an algorithmic framework, capable of protein-ligand homology modelling that brings together new and existing computational routines.…”