Residue Contact Prediction Research Articles

Improving AlphaFold Predicted Contacts for Alpha-Helical Transmembrane Proteins Using Structural Features.

Residue contact maps provide a condensed two-dimensional representation of three-dimensional protein structures, serving as a foundational framework in structural modeling but also as an effective tool in their own right in identifying inter-helical binding sites and drawing insights about protein function. Treating contact maps primarily as an intermediate step for 3D structure prediction, contact prediction methods have limited themselves exclusively to sequential features. Now that AlphaFold2 predicts 3D structures with good accuracy in general, we examine (1) how well predicted 3D structures can be directly used for deciding residue contacts, and (2) whether features from 3D structures can be leveraged to further improve residue contact prediction. With a well-known benchmark dataset, we tested predicting inter-helical residue contact based on AlphaFold2's predicted structures, which gave an 83% average precision, already outperforming a sequential features-based state-of-the-art model. We then developed a procedure to extract features from atomic structure in the neighborhood of a residue pair, hypothesizing that these features will be useful in determining if the residue pair is in contact, provided the structure is decently accurate, such as predicted by AlphaFold2. Training on features generated from experimentally determined structures, we leveraged knowledge from known structures to significantly improve residue contact prediction, when testing using the same set of features but derived using AlphaFold2 structures. Our results demonstrate a remarkable improvement over AlphaFold2, achieving over 91.9% average precision for a held-out subset and over 89.5% average precision in cross-validation experiments.

The Relative Distance Prediction of Transmembrane Protein Surface Residue Based on Improved Residual Networks

(1) Background: Transmembrane proteins (TMPs) act as gateways connecting the intra- and extra-biomembrane environments, exchanging material and signals crossing the biofilm. Relevant evidence shows that corresponding interactions mostly happen on the TMPs’ surface. Therefore, knowledge of the relative distance among surface residues is critically helpful in discovering the potential local structural characters and setting the foundation for the protein’s interaction with other molecules. However, the prediction of fine-grained distances among residues with sequences remains challenging; (2) Methods: In this study, we proposed a deep-learning method called TMP-SurResD, which capitalized on the combination of the Residual Block (RB) and Squeeze-and-Excitation (SE) for simultaneously predicting the relative distance of functional surface residues based on sequences’ information; (3) Results: The comprehensive evaluation demonstrated that TMP-SurResD could successfully capture the relative distance between residues, with a Pearson Correlation Coefficient (PCC) of 0.7105 and 0.6999 on the validation and independent sets, respectively. In addition, TMP-SurResD outperformed other methods when applied to TMPs surface residue contact prediction, and the maximum Matthews Correlation Coefficient (MCC) reached 0.602 by setting a threshold to the predicted distance of 10; (4) Conclusions: TMP-SurResD can serve as a useful tool in supporting a sequence-based local structural feature construction and exploring the function and biological mechanisms of structure determination in TMPs, which can thus significantly facilitate the research direction of molecular drug action, target design, and disease treatment.

Protein Residue Contact Prediction Based on Deep Learning and Massive Statistical Features from Multi-Sequence Alignment

Sequence-based protein tertiary structure prediction is of fundamental importance because the function of a protein ultimately depends on its 3D structure. An accurate residue-residue contact map is one of the essential elements for current ab initio prediction protocols of 3D structure prediction. Recently, with the combination of deep learning and direct coupling techniques, the performance of residue contact prediction has achieved significant progress. However, a considerable number of current Deep-Learning (DL)-based prediction methods are usually time-consuming, mainly because they rely on different categories of data types and third-party programs. In this research, we transformed the complex biological problem into a pure computational problem through statistics and artificial intelligence. We have accordingly proposed a feature extraction method to obtain various categories of statistical information from only the multi-sequence alignment, followed by training a DL model for residue-residue contact prediction based on the massive statistical information. The proposed method is robust in terms of different test sets, showed high reliability on model confidence score, could obtain high computational efficiency and achieve comparable prediction precisions with DL methods that relying on multi-source inputs.

Applications of residue contact predictions in structural biology

Applications of residue contact predictions in structural biology

An interpretable machine learning method for homo-trimeric protein interface residue-residue interaction prediction

Protein-protein interaction plays an important role in life activities. A more fine-grained analysis, such as residues and atoms level, will better benefit us to understand the mechanism for inter-protein interaction and drug design. The development of efficient computational methods to reduce trials and errors, as well as assisting experimental researchers to determine the complex structure are some of the ongoing studies in the field. The research of trimer protein interface, especially homotrimer, has been rarely studied. In this paper, we proposed an interpretable machine learning method for homo-trimeric protein interface residue pairs prediction. The structure, sequence, and physicochemical information are intergraded as feature input fed to model for training. Graph model is utilized to present spatial information for intra-protein. Matrix factorization captures the different features' interactions. Kernel function is designed to auto-acquire the adjacent information of our target residue pairs. The accuracy rate achieves 54.5% in an independent test set. Sequence and structure alignment exhibit the ability of model self-study. Our model indicates the biological significance between sequence and structure, and could be auxiliary for reducing trials and errors in the fields of protein complex determination and protein-protein docking, etc. SignificanceProtein complex structures are significant for understanding protein function and promising functional protein design. With data increasing, some computational tools have been developed for protein complex residue contact prediction, which is one of the most significant steps for complex structure prediction. But for homo-trimeric protein, the sequence-based deep learning predictors are infeasible for homologous sequences, and the algorithm black box prevents us from understanding of each step operation. In this way, we propose an interpreting machine learning method for homo-trimeric protein interface residue-residue interaction prediction, and the predictor shows a good performance. Our work provides a computational auxiliary way for determining the homo-trimeric proteins interface residue pairs which will be further verified by wet experiments, and and gives a hand for the downstream works, such as protein-protein docking, protein complex structure prediction and drug design.

COMTOP: Protein Residue-Residue Contact Prediction through Mixed Integer Linear Optimization.

Protein contact prediction helps reconstruct the tertiary structure that greatly determines a protein’s function; therefore, contact prediction from the sequence is an important problem. Recently there has been exciting progress on this problem, but many of the existing methods are still low quality of prediction accuracy. In this paper, we present a new mixed integer linear programming (MILP)-based consensus method: a Consensus scheme based On a Mixed integer linear opTimization method for prOtein contact Prediction (COMTOP). The MILP-based consensus method combines the strengths of seven selected protein contact prediction methods, including CCMpred, EVfold, DeepCov, NNcon, PconsC4, plmDCA, and PSICOV, by optimizing the number of correctly predicted contacts and achieving a better prediction accuracy. The proposed hybrid protein residue–residue contact prediction scheme was tested in four independent test sets. For 239 highly non-redundant proteins, the method showed a prediction accuracy of 59.68%, 70.79%, 78.86%, 89.04%, 94.51%, and 97.35% for top-5L, top-3L, top-2L, top-L, top-L/2, and top-L/5 contacts, respectively. When tested on the CASP13 and CASP14 test sets, the proposed method obtained accuracies of 75.91% and 77.49% for top-L/5 predictions, respectively. COMTOP was further tested on 57 non-redundant α-helical transmembrane proteins and achieved prediction accuracies of 64.34% and 73.91% for top-L/2 and top-L/5 predictions, respectively. For all test datasets, the improvement of COMTOP in accuracy over the seven individual methods increased with the increasing number of predicted contacts. For example, COMTOP performed much better for large number of contact predictions (such as top-5L and top-3L) than for small number of contact predictions such as top-L/2 and top-L/5. The results and analysis demonstrate that COMTOP can significantly improve the performance of the individual methods; therefore, COMTOP is more robust against different types of test sets. COMTOP also showed better/comparable predictions when compared with the state-of-the-art predictors.

Evaluation of residue-residue contact prediction methods: From retrospective to prospective.

Sequence-based residue contact prediction plays a crucial role in protein structure reconstruction. In recent years, the combination of evolutionary coupling analysis (ECA) and deep learning (DL) techniques has made tremendous progress for residue contact prediction, thus a comprehensive assessment of current methods based on a large-scale benchmark data set is very needed. In this study, we evaluate 18 contact predictors on 610 non-redundant proteins and 32 CASP13 targets according to a wide range of perspectives. The results show that different methods have different application scenarios: (1) DL methods based on multi-categories of inputs and large training sets are the best choices for low-contact-density proteins such as the intrinsically disordered ones and proteins with shallow multi-sequence alignments (MSAs). (2) With at least 5L (L is sequence length) effective sequences in the MSA, all the methods show the best performance, and methods that rely only on MSA as input can reach comparable achievements as methods that adopt multi-source inputs. (3) For top L/5 and L/2 predictions, DL methods can predict more hydrophobic interactions while ECA methods predict more salt bridges and disulfide bonds. (4) ECA methods can detect more secondary structure interactions, while DL methods can accurately excavate more contact patterns and prune isolated false positives. In general, multi-input DL methods with large training sets dominate current approaches with the best overall performance. Despite the great success of current DL methods must be stated the fact that there is still much room left for further improvement: (1) With shallow MSAs, the performance will be greatly affected. (2) Current methods show lower precisions for inter-domain compared with intra-domain contact predictions, as well as very high imbalances in precisions between intra-domains. (3) Strong prediction similarities between DL methods indicating more feature types and diversified models need to be developed. (4) The runtime of most methods can be further optimized.

ModFOLD8: accurate global and local quality estimates for 3D protein models.

Methods for estimating the quality of 3D models of proteins are vital tools for driving the acceptance and utility of predicted tertiary structures by the wider bioscience community. Here we describe the significant major updates to ModFOLD, which has maintained its position as a leading server for the prediction of global and local quality of 3D protein models, over the past decade (>20 000 unique external users). ModFOLD8 is the latest version of the server, which combines the strengths of multiple pure-single and quasi-single model methods. Improvements have been made to the web server interface and there has been successive increases in prediction accuracy, which were achieved through integration of newly developed scoring methods and advanced deep learning-based residue contact predictions. Each version of the ModFOLD server has been independently blind tested in the biennial CASP experiments, as well as being continuously evaluated via the CAMEO project. In CASP13 and CASP14, the ModFOLD7 and ModFOLD8 variants ranked among the top 10 quality estimation methods according to almost every official analysis. Prior to CASP14, ModFOLD8 was also applied for the evaluation of SARS-CoV-2 protein models as part of CASP Commons 2020 initiative. The ModFOLD8 server is freely available at: https://www.reading.ac.uk/bioinf/ModFOLD/.

Protein contact map refinement for improving structure prediction using generative adversarial networks.

Protein structure prediction remains as one of the most important problems in computational biology and biophysics. In the past few years, protein residue-residue contact prediction has undergone substantial improvement, which has made it a critical driving force for successful protein structure prediction. Boosting the accuracy of contact predictions has, therefore, become the forefront of protein structure prediction. We show a novel contact map refinement method, ContactGAN, which uses Generative Adversarial Networks (GAN). ContactGAN was able to make a significant improvement over predictions made by recent contact prediction methods when tested on three datasets including protein structure modeling targets in CASP13 and CASP14. We show improvement of precision in contact prediction, which translated into improvement in the accuracy of protein tertiary structure models. On the other hand, observed improvement over trRosetta was relatively small, reasons for which are discussed. ContactGAN will be a valuable addition in the structure prediction pipeline to achieve an extra gain in contact prediction accuracy. https://github.com/kiharalab/ContactGAN. Supplementary data are available at Bioinformatics online.

Fold recognition by scoring protein maps using the congruence coefficient.

Protein fold recognition is a key step for template-based modeling approaches to protein structure prediction. Although closely related folds can be easily identified by sequence homology search in sequence databases, fold recognition is notoriously more difficult when it involves the identification of distantly related homologs. Recent progress in residue-residue contact and distance prediction opens up the possibility of improving fold recognition by using structural information contained in predicted distance and contact maps. Here we propose to use the congruence coefficient as a metric of similarity between maps. We prove that this metric has several interesting mathematical properties which allow one to compute in polynomial time its exact mean and variance over all possible (exponentially many) alignments between two symmetric matrices, and assess the statistical significance of similarity between aligned maps. We perform fold recognition tests by recovering predicted target contact/distance maps from the two most recent Critical Assessment of Structure Prediction editions and over 27 000 non-homologous structural templates from the ECOD database. On this large benchmark, we compare fold recognition performances of different alignment tools with their own similarity scores against those obtained using the congruence coefficient. We show that the congruence coefficient overall improves fold recognition over other methods, proving its effectiveness as a general similarity metric for protein map comparison. The congruence coefficient software CCpro is available as part of the SCRATCH suite at: http://scratch.proteomics.ics.uci.edu/. Supplementary data are available at Bioinformatics online.

DeepHelicon: Accurate prediction of inter-helical residue contacts in transmembrane proteins by residual neural networks

Accurate prediction of amino acid residue contacts is an important prerequisite for generating high-quality 3D models of transmembrane (TM) proteins. While a large number of compositional, evolutionary, and structural properties of proteins can be used to train contact prediction methods, recent research suggests that coevolution between residues provides the strongest indication of their spatial proximity. We have developed a deep learning approach, DeepHelicon, to predict inter-helical residue contacts in TM proteins by considering only coevolutionary features. DeepHelicon comprises a two-stage supervised learning process by residual neural networks for a gradual refinement of contact maps, followed by variance reduction by an ensemble of models. We present a benchmark study of 12 contact predictors and conclude that DeepHelicon together with the two other state-of-the-art methods DeepMetaPSICOV and Membrain2 outperforms the 10 remaining algorithms on all datasets and at all settings. On a set of 44 TM proteins with an average length of 388 residues DeepHelicon achieves the best performance among all benchmarked methods in predicting the top L/5 and L/2 inter-helical contacts, with the mean precision of 87.42% and 77.84%, respectively. On a set of 57 relatively small TM proteins with an average length of 298 residues DeepHelicon ranks second best after DeepMetaPSICOV. DeepHelicon produces the most accurate predictions for large proteins with more than 10 transmembrane helices. Coevolutionary features alone allow to predict inter-helical residue contacts with an accuracy sufficient for generating acceptable 3D models for up to 30% of proteins using a fully automated modeling method such as CONFOLD2.

SSCpred: Single-Sequence-Based Protein Contact Prediction Using Deep Fully Convolutional Network.

There has been a significant improvement in protein residue contact prediction in recent years. Nevertheless, state-of-the-art methods still show deficiencies in the contact prediction of proteins with low-homology information. These top methods depend largely on statistical features that derived from homologous sequences, but previous studies, along with our analyses, show that they are insufficient for inferencing an accurate contact map for nonhomology protein targets. To compensate, we proposed a brand new single-sequence-based contact predictor (SSCpred) that performs prediction through the deep fully convolutional network (Deep FCN) with only the target sequence itself, i.e., without additional homology information. The proposed pipeline makes good use of the target sequence by utilizing the pair-wise encoding technique and Deep FCN. Experimental results demonstrated that SSCpred can produce accurate predictions based on the efficient pipeline. Compared with several most recent methods, SSCpred achieves completive performance on nonhomology targets. Overall, we explored the possibilities of single-sequence-based contact prediction and designed a novel pipeline without using a complex and redundant feature set. The proposed SSCpred can compensate for current methods' disadvantages and achieves better performance on the nonhomology targets. The web server of SSCpred is freely available at http://csbio.njust.edu.cn/bioinf/sscpred/.

Protein contact prediction using metagenome sequence data and residual neural networks.

Almost all protein residue contact prediction methods rely on the availability of deep multiple sequence alignments (MSAs). However, many proteins from the poorly populated families do not have sufficient number of homologs in the conventional UniProt database. Here we aim to solve this issue by exploring the rich sequence data from the metagenome sequencing projects. Based on the improved MSA constructed from the metagenome sequence data, we developed MapPred, a new deep learning-based contact prediction method. MapPred consists of two component methods, DeepMSA and DeepMeta, both trained with the residual neural networks. DeepMSA was inspired by the recent method DeepCov, which was trained on 441 matrices of covariance features. By considering the symmetry of contact map, we reduced the number of matrices to 231, which makes the training more efficient in DeepMSA. Experiments show that DeepMSA outperforms DeepCov by 10-13% in precision. DeepMeta works by combining predicted contacts and other sequence profile features. Experiments on three benchmark datasets suggest that the contribution from the metagenome sequence data is significant with P-values less than 4.04E-17. MapPred is shown to be complementary and comparable the state-of-the-art methods. The success of MapPred is attributed to three factors: the deeper MSA from the metagenome sequence data, improved feature design in DeepMSA and optimized training by the residual neural networks. http://yanglab.nankai.edu.cn/mappred/. Supplementary data are available at Bioinformatics online.

BetaDL: A protein beta-sheet predictor utilizing a deep learning model and independent set solution

The sequence-based prediction of beta-residue contacts and beta-sheet structures contain key information for protein structure prediction. However, the determination of beta-sheet structures poses numerous challenges due to long-range beta-residue interactions and the huge number of possible beta-sheet structures. Recently gaining attention has been the prediction of residue contacts based on deep learning models whose results have led to improvement in protein structure prediction. In addition, to reduce the computational complexity of determining beta-sheet structures, it has been suggested that this problem be transformed into graph-based solutions. Consequently, the current work proposes BetaDL, a combination of a deep learning and a graph-based beta-sheet structure predictor. BetaDL adopts deep learning models to capture beta-residue contacts and improve beta-sheet structure predictions. In addition, a graph-based approach is presented to model the beta-sheets conformational space and a new score function is introduced to evaluate beta-sheets. Furthermore, the present study demonstrates that the beta-sheet structure can be predicted within an acceptable computational time by the utilization of a heuristic maximum weight independent set solution. When compared to state-of-the-art methods, experimental results from BetaSheet916 and BetaSheet1452 datasets indicate that BetaDL improves the accuracy of beta-residue contact and beta-sheet structure prediction. Using BetaDL, beta-sheet structures are predicted with a 4% and 6% improvement in the F1-score at the residue and strand levels, respectively. BetaDL's source code and data are available at http://kerg.um.ac.ir/index.php/datasets/#BetaDL.

Bio-knowledge-based filters improve residue-residue contact prediction accuracy.

Residue-residue contact prediction through direct coupling analysis has reached impressive accuracy, but yet higher accuracy will be needed to allow for routine modelling of protein structures. One way to improve the prediction accuracy is to filter predicted contacts using knowledge about the particular protein of interest or knowledge about protein structures in general. We focus on the latter and discuss a set of filters that can be used to remove false positive contact predictions. Each filter depends on one or a few cut-off parameters for which the filter performance was investigated. Combining all filters while using default parameters resulted for a test set of 851 protein domains in the removal of 29% of the predictions of which 92% were indeed false positives. All data and scripts are available at http://comprec-lin.iiar.pwr.edu.pl/FPfilter/. Supplementary data are available at Bioinformatics online.

Identification of residue pairing in interacting \u03b2-strands from a predicted residue contact map

BackgroundDespite the rapid progress of protein residue contact prediction, predicted residue contact maps frequently contain many errors. However, information of residue pairing in β strands could be extracted from a noisy contact map, due to the presence of characteristic contact patterns in β-β interactions. This information may benefit the tertiary structure prediction of mainly β proteins. In this work, we propose a novel ridge-detection-based β-β contact predictor to identify residue pairing in β strands from any predicted residue contact map.ResultsOur algorithm RDb2C adopts ridge detection, a well-developed technique in computer image processing, to capture consecutive residue contacts, and then utilizes a novel multi-stage random forest framework to integrate the ridge information and additional features for prediction. Starting from the predicted contact map of CCMpred, RDb2C remarkably outperforms all state-of-the-art methods on two conventional test sets of β proteins (BetaSheet916 and BetaSheet1452), and achieves F1-scores of ~ 62% and ~ 76% at the residue level and strand level, respectively. Taking the prediction of the more advanced RaptorX-Contact as input, RDb2C achieves impressively higher performance, with F1-scores reaching ~ 76% and ~ 86% at the residue level and strand level, respectively. In a test of structural modeling using the top 1 L predicted contacts as constraints, for 61 mainly β proteins, the average TM-score achieves 0.442 when using the raw RaptorX-Contact prediction, but increases to 0.506 when using the improved prediction by RDb2C.ConclusionOur method can significantly improve the prediction of β-β contacts from any predicted residue contact maps. Prediction results of our algorithm could be directly applied to effectively facilitate the practical structure prediction of mainly β proteins.AvailabilityAll source data and codes are available at http://166.111.152.91/Downloads.html or the GitHub address of https://github.com/wzmao/RDb2C.

Three-body interactions improve contact prediction within direct-coupling analysis.

The prediction of residue contacts in a protein solely from sequence information is a promising approach to computational structure prediction. Recent developments use statistical or information theoretic methods to extract contact information from a multiple sequence alignment. Despite good results, accuracy is limited due to usage of two-body interactions within a Potts model. In this paper we generalize this approach and propose a Hamiltonian with an additional three-body interaction term. We derive a mean-field approximation for inference of three-body couplings within a Potts model which is fast enough on modern computers. Finally, we show that our model has a higher accuracy in predicting residue contacts in comparison with the plain two-body-interactionmodel.

MemBrain-contact 2.0: a new two-stage machine learning model for the prediction enhancement of transmembrane protein residue contacts in the full chain.

Inter-residue contacts in proteins have been widely acknowledged to be valuable for protein 3 D structure prediction. Accurate prediction of long-range transmembrane inter-helix residue contacts can significantly improve the quality of simulated membrane protein models. In this paper, we present an updated MemBrain predictor, which aims to predict transmembrane protein residue contacts. Our new model benefits from an efficient learning algorithm that can mine latent structural features, which exist in original feature space. The new MemBrain is a two-stage inter-helix contact predictor. The first stage takes sequence-based features as inputs and outputs coarse contact probabilities for each residue pair, which will be further fed into convolutional neural network together with predictions from three direct-coupling analysis approaches in the second stage. Experimental results on the training dataset show that our method achieves an average accuracy of 81.6% for the top L/5 predictions using a strict sequence-based jackknife cross-validation. Evaluated on the test dataset, MemBrain can achieve 79.4% prediction accuracy. Moreover, for the top L/5 predicted long-range loop contacts, the prediction performance can reach an accuracy of 56.4%. These results demonstrate that the new MemBrain is promising for transmembrane protein's contact map prediction. http://www.csbio.sjtu.edu.cn/bioinf/MemBrain/. Supplementary data are available at Bioinformatics online.

Predicting accurate contacts in thousands of Pfam domain families using PconsC3.

A few years ago it was shown that by using a maximum entropy approach to describe couplings between columns in a multiple sequence alignment it is possible to significantly increase the accuracy of residue contact predictions. For very large protein families with more than 1000 effective sequences the accuracy is sufficient to produce accurate models of proteins as well as complexes. Today, for about half of all Pfam domain families no structure is known, but unfortunately most of these families have at most a few hundred members, i.e. are too small for such contact prediction methods. To extend accurate contact predictions to the thousands of smaller protein families we present PconsC3, a fast and improved method for protein contact predictions that can be used for families with even 100 effective sequence members. PconsC3 outperforms direct coupling analysis (DCA) methods significantly independent on family size, secondary structure content, contact range, or the number of selected contacts. PconsC3 is available as a web server and downloadable version at http://c3.pcons.net . The downloadable version is free for all to use and licensed under the GNU General Public License, version 2. At this site contact predictions for most Pfam families are also available. We do estimate that more than 4000 contact maps for Pfam families of unknown structure have more than 50% of the top-ranked contacts predicted correctly. arne@bioinfo.se. Supplementary data are available at Bioinformatics online.

A deep learning framework for improving long-range residue-residue contact prediction using a hierarchical strategy.

Residue-residue contacts are of great value for protein structure prediction, since contact information, especially from those long-range residue pairs, can significantly reduce the complexity of conformational sampling for protein structure prediction in practice. Despite progresses in the past decade on protein targets with abundant homologous sequences, accurate contact prediction for proteins with limited sequence information is still far from satisfaction. Methodologies for these hard targets still need further improvement. We presented a computational program DeepConPred, which includes a pipeline of two novel deep-learning-based methods (DeepCCon and DeepRCon) as well as a contact refinement step, to improve the prediction of long-range residue contacts from primary sequences. When compared with previous prediction approaches, our framework employed an effective scheme to identify optimal and important features for contact prediction, and was only trained with coevolutionary information derived from a limited number of homologous sequences to ensure robustness and usefulness for hard targets. Independent tests showed that 59.33%/49.97%, 64.39%/54.01% and 70.00%/59.81% of the top L/5, top L/10 and top 5 predictions were correct for CASP10/CASP11 proteins, respectively. In general, our algorithm ranked as one of the best methods for CASP targets. All source data and codes are available at http://166.111.152.91/Downloads.html . hgong@tsinghua.edu.cn or zengjy321@tsinghua.edu.cn. Supplementary data are available at Bioinformatics online.