Inter-protein Contact Prediction Research Articles

Protein language model-embedded geometric graphs power inter-protein contact prediction

Accurate prediction of contacting residue pairs between interacting proteins is very useful for structural characterization of protein–protein interactions. Although significant improvement has been made in inter-protein contact prediction recently, there is still a large room for improving the prediction accuracy. Here we present a new deep learning method referred to as PLMGraph-Inter for inter-protein contact prediction. Specifically, we employ rotationally and translationally invariant geometric graphs obtained from structures of interacting proteins to integrate multiple protein language models, which are successively transformed by graph encoders formed by geometric vector perceptrons and residual networks formed by dimensional hybrid residual blocks to predict inter-protein contacts. Extensive evaluation on multiple test sets illustrates that PLMGraph-Inter outperforms five top inter-protein contact prediction methods, including DeepHomo, GLINTER, CDPred, DeepHomo2, and DRN-1D2D_Inter, by large margins. In addition, we also show that the prediction of PLMGraph-Inter can complement the result of AlphaFold-Multimer. Finally, we show leveraging the contacts predicted by PLMGraph-Inter as constraints for protein–protein docking can dramatically improve its performance for protein complex structure prediction.

Protein language model-embedded geometric graphs power inter-protein contact prediction.

Accurate prediction of contacting residue pairs between interacting proteins is very useful for structural characterization of protein-protein interactions. Although significant improvement has been made in inter-protein contact prediction recently, there is still a large room for improving the prediction accuracy. Here we present a new deep learning method referred to as PLMGraph-Inter for inter-protein contact prediction. Specifically, we employ rotationally and translationally invariant geometric graphs obtained from structures of interacting proteins to integrate multiple protein language models, which are successively transformed by graph encoders formed by geometric vector perceptrons and residual networks formed by dimensional hybrid residual blocks to predict inter-protein contacts. Extensive evaluation on multiple test sets illustrates that PLMGraph-Inter outperforms five top inter-protein contact prediction methods, including DeepHomo, GLINTER, CDPred, DeepHomo2, and DRN-1D2D_Inter, by large margins. In addition, we also show that the prediction of PLMGraph-Inter can complement the result of AlphaFold-Multimer. Finally, we show leveraging the contacts predicted by PLMGraph-Inter as constraints for protein-protein docking can dramatically improve its performance for protein complex structure prediction.

Improved inter-protein contact prediction using dimensional hybrid residual networks and protein language models.

The knowledge of contacting residue pairs between interacting proteins is very useful for the structural characterization of protein-protein interactions (PPIs). However, accurately identifying the tens of contacting ones from hundreds of thousands of inter-protein residue pairs is extremely challenging, and performances of the state-of-the-art inter-protein contact prediction methods are still quite limited. In this study, we developed a deep learning method for inter-protein contact prediction, which is referred to as DRN-1D2D_Inter. Specifically, we employed pretrained protein language models to generate structural information-enriched input features to residual networks formed by dimensional hybrid residual blocks to perform inter-protein contact prediction. Extensively bechmarking DRN-1D2D_Inter on multiple datasets, including both heteromeric PPIs and homomeric PPIs, we show DRN-1D2D_Inter consistently and significantly outperformed two state-of-the-art inter-protein contact prediction methods, including GLINTER and DeepHomo, although both the latter two methods leveraged the native structures of interacting proteins in the prediction, and DRN-1D2D_Inter made the prediction purely from sequences. We further show that applying the predicted contacts as constraints for protein-protein docking can significantly improve its performance for protein complex structure prediction.

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

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/

Chasing coevolutionary signals in intrinsically disordered proteins complexes

Intrinsically disordered proteins/regions (IDPs/IDRs) are crucial components of the cell, they are highly abundant and participate ubiquitously in a wide range of biological functions, such as regulatory processes and cell signaling. Many of their important functions rely on protein interactions, by which they trigger or modulate different pathways. Sequence covariation, a powerful tool for protein contact prediction, has been applied successfully to predict protein structure and to identify protein–protein interactions mostly of globular proteins. IDPs/IDRs also mediate a plethora of protein–protein interactions, highlighting the importance of addressing sequence covariation-based inter-protein contact prediction of this class of proteins. Despite their importance, a systematic approach to analyze the covariation phenomena of intrinsically disordered proteins and their complexes is still missing. Here we carry out a comprehensive critical assessment of coevolution-based contact prediction in IDP/IDR complexes and detail the challenges and possible limitations that emerge from their analysis. We found that the coevolutionary signal is faint in most of the complexes of disordered proteins but positively correlates with the interface size and binding affinity between partners. In addition, we discuss the state-of-art methodology by biological interpretation of the results, formulate evaluation guidelines and suggest future directions of development to the field.

A Web-Based Protocol for Interprotein Contact Prediction by Deep Learning.

Identifying residue-residue contacts in protein-protein interactions or complex is crucial for understanding protein and cell functions. DCA (direct-coupling analysis) methods shed some light on this, but they need many sequence homologs to yield accurate prediction. Inspired by the success of our deep-learning method for intraprotein contact prediction, we have developed RaptorX-ComplexContact, a web server for interprotein residue-residue contact prediction. Given a pair of interacting protein sequences, RaptorX-ComplexContact first searches for their sequence homologs and builds two paired multiple sequence alignments (MSA) based on genomic distance and phylogeny information, respectively. Then, RaptorX-ComplexContact uses two deep convolutional residual neural networks (ResNet) to predict interprotein contacts from sequential features and coevolution information of paired MSAs. RaptorX-ComplexContact shall be useful for protein docking, protein-protein interaction prediction, and protein interaction network construction.

ComplexContact: a web server for inter-protein contact prediction using deep learning.

ComplexContact (http://raptorx2.uchicago.edu/ComplexContact/) is a web server for sequence-based interfacial residue-residue contact prediction of a putative protein complex. Interfacial residue-residue contacts are critical for understanding how proteins form complex and interact at residue level. When receiving a pair of protein sequences, ComplexContact first searches for their sequence homologs and builds two paired multiple sequence alignments (MSA), then it applies co-evolution analysis and a CASP-winning deep learning (DL) method to predict interfacial contacts from paired MSAs and visualizes the prediction as an image. The DL method was originally developed for intra-protein contact prediction and performed the best in CASP12. Our large-scale experimental test further shows that ComplexContact greatly outperforms pure co-evolution methods for inter-protein contact prediction, regardless of the species.

I-COMS: Interprotein-COrrelated Mutations Server.

Interprotein contact prediction using multiple sequence alignments (MSAs) is a useful approach to help detect protein–protein interfaces. Different computational methods have been developed in recent years as an approximation to solve this problem. However, as there are discrepancies in the results provided by them, there is still no consensus on which is the best performing methodology. To address this problem, I-COMS (interprotein COrrelated Mutations Server) is presented. I-COMS allows to estimate covariation between residues of different proteins by four different covariation methods. It provides a graphical and interactive output that helps compare results obtained using different methods. I-COMS automatically builds the required MSA for the calculation and produces a rich visualization of either intraprotein and/or interprotein covariating positions in a circos representation. Furthermore, comparison between any two methods is available as well as the overlap between any or all four methodologies. In addition, as a complementary source of information, a matrix visualization of the corresponding scores is made available and the density plot distribution of the inter, intra and inter+intra scores are calculated. Finally, all the results can be downloaded (including MSAs, scores and graphics) for comparison and visualization and/or for further analysis.