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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/.

SUBMITTER: Yan Y

PROVIDER: S-EPMC8425427 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Effective encoding of residue contact information is crucial for protein structure prediction since it has a unique role to capture long-range residue interactions compared to other commonly used scoring terms. The residue contact information can be incorporated in structure prediction in several different ways: It can be incorporated as statistical potentials or it can be also used as constraints in ab initio structure prediction. To seek the most effective definition of residue contacts for template-based protein structure prediction, we evaluated 45 different contact definitions, varying bases of contacts and distance cutoffs, in terms of their ability to identify proteins of the same fold.We found that overall the residue contact pattern can distinguish protein folds best when contacts are defined for residue pairs whose C? atoms are at 7.0 Å or closer to each other. Lower fold recognition accuracy was observed when inaccurate threading alignments were used to identify common residue contacts between protein pairs. In the case of threading, alignment accuracy strongly influences the fraction of common contacts identified among proteins of the same fold, which eventually affects the fold recognition accuracy. The largest deterioration of the fold recognition was observed for ?-class proteins when the threading methods were used because the average alignment accuracy was worst for this fold class. When results of fold recognition were examined for individual proteins, we found that the effective contact definition depends on the fold of the proteins. A larger distance cutoff is often advantageous for capturing spatial arrangement of the secondary structures which are not physically in contact. For capturing contacts between neighboring ? strands, considering the distance between C? atoms is better than the C?-based distance because the side-chain of interacting residues on ? strands sometimes point to opposite directions.Residue contacts defined by C?-C? distance of 7.0 Å work best overall among tested to identify proteins of the same fold. We also found that effective contact definitions differ from fold to fold, suggesting that using different residue contact definition specific for each template will lead to improvement of the performance of threading.

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

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