Prediction Of Protein Interaction Sites Research Articles

Imbalance Data Processing Strategy for Protein Interaction Sites Prediction.

Protein-protein interactions play essential roles in various biological progresses. Identifying protein interaction sites can facilitate researchers to understand life activities and therefore will be helpful for drug design. However, the number of experimental determined protein interaction sites is far less than that of protein sites in protein-protein interaction or protein complexes. Therefore, the negative and positive samples are usually imbalanced, which is common but bring result bias on the prediction of protein interaction sites by computational approaches. In this work, we presented three imbalance data processing strategies to reconstruct the original dataset, and then extracted protein features from the evolutionary conservation of amino acids to build a predictor for identification of protein interaction sites. On a dataset with 10,430 surface residues but only 2,299 interface residues, the imbalance dataset processing strategies can obviously reduce the prediction bias, and therefore improve the prediction performance of protein interaction sites. The experimental results show that our prediction models can achieve a better prediction performance, such as a prediction accuracy of 0.758, or a high F-measure of 0.737, which demonstrated the effectiveness of our method.

DELPHI: accurate deep ensemble model for protein interaction sites prediction.

Proteins usually perform their functions by interacting with other proteins, which is why accurately predicting protein-protein interaction (PPI) binding sites is a fundamental problem. Experimental methods are slow and expensive. Therefore, great efforts are being made towards increasing the performance of computational methods. We propose DEep Learning Prediction of Highly probable protein Interaction sites (DELPHI), a new sequence-based deep learning suite for PPI-binding sites prediction. DELPHI has an ensemble structure which combines a CNN and a RNN component with fine tuning technique. Three novel features, HSP, position information and ProtVec are used in addition to nine existing ones. We comprehensively compare DELPHI to nine state-of-the-art programmes on five datasets, and DELPHI outperforms the competing methods in all metrics even though its training dataset shares the least similarities with the testing datasets. In the most important metrics, AUPRC and MCC, it surpasses the second best programmes by as much as 18.5% and 27.7%, respectively. We also demonstrated that the improvement is essentially due to using the ensemble model and, especially, the three new features. Using DELPHI it is shown that there is a strong correlation with protein-binding residues (PBRs) and sites with strong evolutionary conservation. In addition, DELPHI's predicted PBR sites closely match known data from Pfam. DELPHI is available as open-sourced standalone software and web server. The DELPHI web server can be found at delphi.csd.uwo.ca/, with all datasets and results in this study. The trained models, the DELPHI standalone source code, and the feature computation pipeline are freely available at github.com/lucian-ilie/DELPHI. Supplementary data are available at Bioinformatics online.

DELPHI: accurate deep ensemble model for protein interaction sites prediction

Motivation Proteins usually perform their functions by interacting with other proteins, which is why accurately predicting protein-protein interaction (PPI) binding sites is a fundamental problem. Experimental methods are slow and expensive. Therefore, great efforts are being made towards increasing the performance of computational methods. Results We propose DEep Learning Prediction of Highly probable protein Interaction sites (DELPHI), a new sequence-based deep learning suite for PPI-binding sites prediction. DELPHI has an ensemble structure which combines a CNN and a RNN component with fine tuning technique. Three novel features, HSP, position information and ProtVec are used in addition to nine existing ones. We comprehensively compare DELPHI to nine state-of-the-art programmes on five datasets, and DELPHI outperforms the competing methods in all metrics even though its training dataset shares the least similarities with the testing datasets. In the most important metrics, AUPRC and MCC, it surpasses the second best programmes by as much as 18.5% and 27.7%, respectively. We also demonstrated that the improvement is essentially due to using the ensemble model and, especially, the three new features. Using DELPHI it is shown that there is a strong correlation with protein-binding residues (PBRs) and sites with strong evolutionary conservation. In addition, DELPHI's predicted PBR sites closely match known data from Pfam. DELPHI is available as open-sourced standalone software and web server. Availability and implementation The DELPHI web server can be found at delphi.csd.uwo.ca/, with all datasets and results in this study. The trained models, the DELPHI standalone source code, and the feature computation pipeline are freely available at github.com/lucian-ilie/DELPHI. Supplementary information Supplementary data are available at Bioinformatics online.

Semi-supervised prediction of protein interaction sites from unlabeled sample information

BackgroundThe recognition of protein interaction sites is of great significance in many biological processes, signaling pathways and drug designs. However, most sites on protein sequences cannot be defined as interface or non-interface sites because only a small part of protein interactions had been identified, which will cause the lack of prediction accuracy and generalization ability of predictors in protein interaction sites prediction. Therefore, it is necessary to effectively improve prediction performance of protein interaction sites using large amounts of unlabeled data together with small amounts of labeled data and background knowledge today.ResultsIn this work, three semi-supervised support vector machine–based methods are proposed to improve the performance in the protein interaction sites prediction, in which the information of unlabeled protein sites can be involved. Herein, five features related with the evolutionary conservation of amino acids are extracted from HSSP database and Consurf Sever, i.e., residue spatial sequence spectrum, residue sequence information entropy and relative entropy, residue sequence conserved weight and residual Base evolution rate, to represent the residues within the protein sequence. Then three predictors are built for identifying the interface residues from protein surface using three types of semi-supervised support vector machine algorithms.ConclusionThe experimental results demonstrated that the semi-supervised approaches can effectively improve prediction performance of protein interaction sites when unlabeled information is involved into the predictors and one of them can achieve the best prediction performance, i.e., the accuracy of 70.7%, the sensitivity of 62.67% and the specificity of 78.72%, respectively. With comparison to the existing studies, the semi-supervised models show the improvement of the predication performance.

Stochastic Sensitivity Tree Boosting for Imbalanced Prediction Problems of Protein-Ligand Interaction Sites

Prediction of protein–protein interaction sites plays an important role for understanding the protein interactions and functions. However, in the protein–protein interaction site prediction problem, the number of binding-site residues is usually much less than that of other amino acid residues in a protein chain, which would lead to the performance drop of standard machine learning methods on minority class, i.e., the binding-site residues. Therefore, to improve the prediction performance on binding-site residues, we propose in this paper a new boosting algorithm (SSTBoost) that consists of stochastic sensitivity measure-based undersampling method and AdaBoost algorithm. Stochastic sensitivity measure-based undersampling method aims to re-balance the dataset by selecting those samples with the highest probability to be incorrectly labeled, and AdaBoost algorithm aims to improve the performance of base hypotheses by making them to be complementary and be conjunction with each other. Twenty UCI datasets are first used to evaluate the robustness and effectiveness of the SSTBoost. After that, the SSTBoost is tested on twenty-two practical protein–protein interaction sites prediction problems. Experimental results show that the SSTBoost significantly improves the performances against state-of-the-art methods by <inline-formula xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink"><tex-math notation="LaTeX">$\text{57.3}\%$</tex-math></inline-formula> , <inline-formula xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink"><tex-math notation="LaTeX">$\text{88.2}\%$</tex-math></inline-formula> , and <inline-formula xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink"><tex-math notation="LaTeX">$\text{78.2}\%$</tex-math></inline-formula> out of 110 cases in terms of Recall, F-score, and G-mean, respectively. This shows its potential to handle other bioinformatic applications in near future.

SeRenDIP: SEquential REmasteriNg to DerIve profiles for fast and accurate predictions of PPI interface positions.

Interpretation of ubiquitous protein sequence data has become a bottleneck in biomolecular research, due to a lack of structural and other experimental annotation data for these proteins. Prediction of protein interaction sites from sequence may be a viable substitute. We therefore recently developed a sequence-based random forest method for protein-protein interface prediction, which yielded a significantly increased performance than other methods on both homomeric and heteromeric protein-protein interactions. Here, we present a webserver that implements this method efficiently. With the aim of accelerating our previous approach, we obtained sequence conservation profiles by re-mastering the alignment of homologous sequences found by PSI-BLAST. This yielded a more than 10-fold speedup and at least the same accuracy, as reported previously for our method; these results allowed us to offer the method as a webserver. The web-server interface is targeted to the non-expert user. The input is simply a sequence of the protein of interest, and the output a table with scores indicating the likelihood of having an interaction interface at a certain position. As the method is sequence-based and not sensitive to the type of protein interaction, we expect this webserver to be of interest to many biological researchers in academia and in industry. Webserver, source code and datasets are available at www.ibi.vu.nl/programs/serendipwww/. Supplementary data are available at Bioinformatics online.

Sequence-based prediction of protein-protein interaction sites by simplified long short-term memory network

Proteins often interact with each other and form protein complexes to carry out various biochemical activities. Knowledge of the interaction sites is helpful for understanding disease mechanisms and drug design. Accurate prediction of the interaction sites from protein sequences is still a challenging task and severe imbalance data also decreased the performance of computational methods. In this study, we propose to use a deep learning method for improving the imbalanced prediction of protein interaction sites. We develop a new simplified long short-term memory (SLSTM) network to implement a deep learning architecture (named DLPred). To deal with the imbalanced classification in the deep learning model, we explore three new ideas. First, our collection of the training data is to construct a set of protein sequences, instead of a set of just single residues, to retain the entire sequential completeness of each protein. Second, a new penalization factor is appended to the loss function such that the penalization to the non-interaction site loss can be effectively enhanced. Third, multi-task learning of interaction sites and residue solvent accessibility prediction are used for correcting the preference of the prediction model on the non-interaction sites. Our model is evaluated on three public datasets: Dset186, Dtestset72 and PDBtestset164. Compared with current state-of-the-art methods, DLPred is able to significantly improve the predictive accuracies and AUC values while improving the F-measure. The training dataset, test datasets, a standalone version of DLPred and online service are available at http://qianglab.scst.suda.edu.cn/dlp/.

Protein-protein interaction sites prediction by ensemble random forests with synthetic minority oversampling technique.

The prediction of protein-protein interaction (PPI) sites is a key to mutation design, catalytic reaction and the reconstruction of PPI networks. It is a challenging task considering the significant abundant sequences and the imbalance issue in samples. A new ensemble learning-based method, Ensemble Learning of synthetic minority oversampling technique (SMOTE) for Unbalancing samples and RF algorithm (EL-SMURF), was proposed for PPI sites prediction in this study. The sequence profile feature and the residue evolution rates were combined for feature extraction of neighboring residues using a sliding window, and the SMOTE was applied to oversample interface residues in the feature space for the imbalance problem. The Multi-dimensional Scaling feature selection method was implemented to reduce feature redundancy and subset selection. Finally, the Random Forest classifiers were applied to build the ensemble learning model, and the optimal feature vectors were inserted into EL-SMURF to predict PPI sites. The performance validation of EL-SMURF on two independent validation datasets showed 77.1% and 77.7% accuracy, which were 6.2-15.7% and 6.1-18.9% higher than the other existing tools, respectively. The source codes and data used in this study are publicly available at http://github.com/QUST-AIBBDRC/EL-SMURF/. Supplementary data are available at Bioinformatics online.

Protein–protein interaction sites prediction by ensembling SVM and sample-weighted random forests

Predicting protein–protein interaction (PPI) sites from protein sequences is still a challenge task in computational biology. There exists a severe class imbalance phenomenon in predicting PPI sites, which leads to a decrease in overall performance for traditional statistical machine-learning-based classifiers, such as SVM and random forests. In this study, an ensemble of SVM and sample-weighted random forests (SSWRF) was proposed to deal with class imbalance. An SVM classifier was trained and applied to estimate the weights of training samples. Then, the training samples with estimated weights were utilized to train a sample-weighted random forests (SWRF). In addition, a lower-dimensional feature representation method, which consists of evolutionary conservation, hydrophobic property, solvent accessibility features derived from a target residue and its neighbors, was developed to improve the discriminative capability for PPI sites prediction. The analysis of feature importance shows that the proposed feature representation method is an effective representation for predicting PPI sites. The proposed SSWRF achieved 22.4% and 35.1% in MCC and F-measure, respectively, on independent validation dataset Dtestset72, and achieved 15.2% and 36.5% in MCC and F-measure, respectively, on PDBtestset164. Computational comparisons between existing PPI sites predictors on benchmark datasets demonstrated that the proposed SSWRF is effective for PPI sites prediction and outperforms the state-of-the-art sequence-based method (i.e., LORIS) released most recently. The benchmark datasets used in this study and the source codes of the proposed method are publicly available at http://csbio.njust.edu.cn/bioinf/SSWRF for academic use.

Sequence-based prediction of protein–protein interaction sites with L1-logreg classifier

Protein–protein interactions are of central importance for virtually every process in a living cell. Information about the interaction sites in proteins improves our understanding of disease mechanisms and can provide the basis for new therapeutic approaches. Since a multitude of unique residue–residue contacts facilitate the interactions, protein–protein interaction sites prediction has become one of the most important and challenging problems of computational biology. Although much progress in this field has been reported, this problem is yet to be satisfactorily solved. Here, a novel method (LORIS: L1-regularized LOgistic Regression based protein–protein Interaction Sites predictor) is proposed, that identifies interaction residues, using sequence features and is implemented via the L1-logreg classifier. Results show that LORIS is not only quite effective, but also, performs better than existing state-of-the art methods. LORIS, available as standalone package, can be useful for facilitating drug-design and targeted mutation related studies, which require a deeper knowledge of protein interactions sites.

A novel method for prediction of protein interaction sites based on integrated RBF neural networks

Protein interactions are very important for control life activities. If we want to study the principle of protein interactions, we have to find the seats of a protein which are involved in the interactions called interaction sites firstly. In this paper, a novel method based on an integrated RBF neural networks is proposed for prediction of protein interaction sites. At first, a number of features were extracted, i.e., sequence profiles, entropy, relative entropy, conservation weight, accessible surface area and sequence variability. Then 6 sliding windows about these features were made, and they contained 1, 3, 5, 7, 9 and 11 amino acid residues respectively. These sliding windows were put into the input layers of six radial basis functional neural networks that were optimized by Particle Swarm Optimization. Thus, six group results were obtained. Finally, these six group results were integrated by decision fusion (DF) and Genetic Algorithm based Selective Ensemble (GASEN). The experimental results show that the proposed method performs better than the other related methods such as neural networks and support vector machine.

Radial Basis Function Neural Network Ensemble for Predicting Protein-Protein Interaction Sites in Heterocomplexes

Prediction of protein-protein interaction sites can guide the structural elucidation of protein complexes. We propose a novel method using a radial basis function neural network (RBFNN) ensemble model for the prediction of protein interaction sites in heterocomplexes. We classified protein surface residues into interaction sites or non-interaction sites based on the RBFNNs trained on different datasets, then judged a prediction to be the final output. Only information of evolutionary conservation and spatial sequence profile are used in this ensemble predictor to describe the protein sites. A non-redundant data set of heterodimers used is consisted of 69 protein chains, in which 10329 surface residues can be found. The efficiency and the effectiveness of our proposed approach can be validated by a better performance such as the accuracy of 0.689, the sensitivity of 66.6% and the specificity of 67.6%.

Sequence-based prediction of protein interaction sites with an integrative method

Identification of protein interaction sites has significant impact on understanding protein function, elucidating signal transduction networks and drug design studies. With the exponentially growing protein sequence data, predictive methods using sequence information only for protein interaction site prediction have drawn increasing interest. In this article, we propose a predictive model for identifying protein interaction sites. Without using any structure data, the proposed method extracts a wide range of features from protein sequences. A random forest-based integrative model is developed to effectively utilize these features and to deal with the imbalanced data classification problem commonly encountered in binding site predictions. We evaluate the predictive method using 2829 interface residues and 24,616 non-interface residues extracted from 99 polypeptide chains in the Protein Data Bank. The experimental results show that the proposed method performs significantly better than two other sequence-based predictive methods and can reliably predict residues involved in protein interaction sites. Furthermore, we apply the method to predict interaction sites and to construct three protein complexes: the DnaK molecular chaperone system, 1YUW and 1DKG, which provide new insight into the sequence-function relationship. We show that the predicted interaction sites can be valuable as a first approach for guiding experimental methods investigating protein-protein interactions and localizing the specific interface residues. Datasets and software are available at http://ittc.ku.edu/~xwchen/bindingsite/prediction.

Prediction of Protein Interaction Sites and Protein-Protein Interaction Pairs Using Support Vector Machines

Prediction of Protein Interaction Sites and Protein-Protein Interaction Pairs Using Support Vector Machines

Prediction of protein interaction sites from sequence profile and residue neighbor list.

Protein-protein interaction sites are predicted from a neural network with sequence profiles of neighboring residues and solvent exposure as input. The network was trained on 615 pairs of nonhomologous complex-forming proteins. Tested on a different set of 129 pairs of nonhomologous complex-forming proteins, 70% of the 11,004 predicted interface residues are actually located in the interfaces. These 7732 correctly predicted residues account for 65% of the 11,805 residues making up the 129 interfaces. The main strength of the network predictor lies in the fact that neighbor lists and solvent exposure are relatively insensitive to structural changes accompanying complex formation. As such, it performs equally well with bound or unbound structures of the proteins. For a set of 35 test proteins, when the input was calculated from the bound and unbound structures, the correct fractions of the predicted interface residues were 69 and 70%, respectively.