Q-BioLiP: A Comprehensive Resource for Quaternary Structure-based Protein–ligand Interactions

Abstract

Since its establishment in 2013, BioLiP has become one of the widely used resources for protein–ligand interactions. Nevertheless, several known issues occurred with it over the past decade. For example, the protein–ligand interactions are represented in the form of single chain-based tertiary structures, which may be inappropriate as many interactions involve multiple protein chains (known as quaternary structures). We sought to address these issues, resulting in Q-BioLiP, a comprehensive resource for quaternary structure-based protein–ligand interactions. The major features of Q-BioLiP include: (1) representing protein structures in the form of quaternary structures rather than single chain-based tertiary structures; (2) pairing DNA/RNA chains properly rather than separation; (3) providing both experimental and predicted binding affinities; (4) retaining both biologically relevant and irrelevant interactions to alleviate the wrong justification of ligands’ biological relevance; and (5) developing a new quaternary structure-based algorithm for the modelling of protein–ligand complex structure. With these new features, Q-BioLiP is expected to be a valuable resource for studying biomolecule interactions, including protein–small molecule interaction, protein–metal ion interaction, protein–peptide interaction, protein–protein interaction, protein–DNA/RNA interaction, and RNA–small molecule interaction. Q-BioLiP is freely available at https://yanglab.qd.sdu.edu.cn/Q-BioLiP/.

1. Introduction

The biological functions of many proteins are achieved by interacting with other biomolecules, which are referred to as ligands. A collection of high-quality data for protein–ligand interactions is essential to enable related computational studies, such as in the prediction of protein–ligand binding sites, the prediction of binding affinity, and protein–ligand docking. BioLiP is a database that collects 3-dimensional (3D) structures of biologically relevant protein–ligand interactions. It has emerged as one of the most widely used resources for investigating protein–ligand interactions.

There are several known inherent issues with the data in BioLiP. First, the protein structures in BioLiP are represented in single chain-based tertiary structures. Nonetheless, the functional form of many proteins is in quaternary structures, typically comprising multiple interacting chains. Consequently, some vital protein–ligand interactions are not captured in the BioLiP data due to the incompleteness of the protein structure, particularly when a ligand simultaneously interacts with multiple protein chains. For example, the hemoglobin protein can only transport oxygen in the form of a tetramer, which is composed of four chains. Second, DNA ligands in BioLiP are presented in a single-chain format, which is inconsistent with the fact that DNA typically forms a double-helix structure consisting of two complementary chains. The third issue is the potential misjudgement of the biological relevance. BioLiP employs an empirical rule to determine whether a protein–ligand interaction is biologically relevant or not. Consequently, a protein–ligand interaction that is deemed biologically irrelevant is excluded from BioLiP, resulting in the problem of missing data, when a biologically relevant interaction is mistakenly judged as irrelevant.