Development of a protein-ligand-binding site prediction method based on interaction energy and sequence conservation.

Kazuya Sumikoshi,Cao Wei,Gul Saad,Tohru Terada,Shugo Nakamura,Hiroto Tsujikawa,Kenta Sato,Kentaro Shimizu

doi:10.1007/s10969-016-9204-2

Kazuya Sumikoshi, Cao Wei + Show 6 more

Open Access

https://doi.org/10.1007/s10969-016-9204-2

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Abstract

We present a new method for predicting protein–ligand-binding sites based on protein three-dimensional structure and amino acid conservation. This method involves calculation of the van der Waals interaction energy between a protein and many probes placed on the protein surface and subsequent clustering of the probes with low interaction energies to identify the most energetically favorable locus. In addition, it uses amino acid conservation among homologous proteins. Ligand-binding sites were predicted by combining the interaction energy and the amino acid conservation score. The performance of our prediction method was evaluated using a non-redundant dataset of 348 ligand-bound and ligand-unbound protein structure pairs, constructed by filtering entries in a ligand-binding site structure database, LigASite. Ligand-bound structure prediction (bound prediction) indicated that 74.0 % of predicted ligand-binding sites overlapped with real ligand-binding sites by over 25 % of their volume. Ligand-unbound structure prediction (unbound prediction) indicated that 73.9 % of predicted ligand-binding residues overlapped with real ligand-binding residues. The amino acid conservation score improved the average prediction accuracy by 17.0 and 17.6 points for the bound and unbound predictions, respectively. These results demonstrate the effectiveness of the combined use of the interaction energy and amino acid conservation in the ligand-binding site prediction.Electronic supplementary materialThe online version of this article (doi:10.1007/s10969-016-9204-2) contains supplementary material, which is available to authorized users.

Highlights

It is well known that the biological function of many proteins depends on binding to small molecules, termed ligands
Various methods have been developed for ligand-binding site prediction, and because ligand-binding sites are often located in large depressions on protein surfaces, many of these prediction methods use 3D protein structures to predict ligand-binding sites
Excluding proteins containing over 10,000 atoms, which are not accepted by the Q-SiteFinder server, 342

Summary

Introduction

It is well known that the biological function of many proteins depends on binding to small molecules, termed ligands. The function of a protein can be inferred by determining what kinds of ligands it binds. Various methods have been developed for ligand-binding site prediction, and because ligand-binding sites are often located in large depressions (pockets) on protein surfaces, many of these prediction methods use 3D protein structures to predict ligand-binding sites. These structure-based methods can be largely classified into two groups: (a) purely geometric methods [1,2,3,4] and (b) energetic methods [5, 6]

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