Accurate prediction of inter-protein residue–residue contacts for homo-oligomeric protein complexes

Abstract Protein–protein interactions play a fundamental role in all cellular processes. Therefore, determining the structure of protein–protein complexes is crucial to understand their molecular mechanisms and develop drugs targeting the protein–protein interactions. Recently, deep learning has led to a breakthrough in intra-protein contact prediction, achieving an unusual high accuracy in recent Critical Assessment of protein Structure Prediction (CASP) structure prediction challenges. However, due to the limited number of known homologous protein–protein interactions and the challenge to generate joint multiple sequence alignments of two interacting proteins, the advances in inter-protein contact prediction remain limited. Here, we have proposed a deep learning model to predict inter-protein residue–residue contacts across homo-oligomeric protein interfaces, named as DeepHomo. Unlike previous deep learning approaches, we integrated intra-protein distance map and inter-protein docking pattern, in addition to evolutionary coupling, sequence conservation, and physico-chemical information of monomers. DeepHomo was extensively tested on both experimentally determined structures and realistic CASP-Critical Assessment of Predicted Interaction (CAPRI) targets. It was shown that DeepHomo achieved a high precision of >60% for the top predicted contact and outperformed state-of-the-art direct-coupling analysis and machine learning-based approaches. Integrating predicted inter-chain contacts into protein–protein docking significantly improved the docking accuracy on the benchmark dataset of realistic homo-dimeric targets from CASP-CAPRI experiments. DeepHomo is available at http://huanglab.phys.hust.edu.cn/DeepHomo/