Prediction Of Protein-protein Interaction Sites Research Articles

MEG-PPIS: a fast protein-protein interaction site prediction method based on multi-scale graph information and equivariant graph neural network.

Protein-protein interaction sites (PPIS) are crucial for deciphering protein action mechanisms and related medical research, which is the key issue in protein action research. Recent studies have shown that graph neural networks have achieved outstanding performance in predicting PPIS. However, these studies often neglect the modeling of information at different scales in the graph and the symmetry of protein molecules within three-dimensional space. In response to this gap, this paper proposes the MEG-PPIS approach, a PPIS prediction method based on multi-scale graph information and E(n) equivariant graph neural network (EGNN). There are two channels in MEG-PPIS: the original graph and the subgraph obtained by graph pooling. The model can iteratively update the features of the original graph and subgraph through the weight-sharing EGNN. Subsequently, the max-pooling operation aggregates the updated features of the original graph and subgraph. Ultimately, the model feeds node features into the prediction layer to obtain prediction results. Comparative assessments against other methods on benchmark datasets reveal that MEG-PPIS achieves optimal performance across all evaluation metrics and gets the fastest runtime. Furthermore, specific case studies demonstrate that our method can predict more true positive and true negative sites than the current best method, proving that our model achieves better performance in the PPIS prediction task. The data and code are available at https://github.com/dhz234/MEG-PPIS.git.

Protein-Protein Interaction Site Prediction Based on Attention Mechanism and Convolutional Neural Networks.

Proteins usually perform their cellular functions by interacting with other proteins. Accurate identification of protein-protein interaction sites (PPIs) from sequence is import for designing new drugs and developing novel therapeutics. A lot of computational models for PPIs prediction have been developed because experimental methods are slow and expensive. Most models employ a sliding window approach in which local neighbors are concatenated to present a target residue. However, those neighbors are not distinguished by pairwise information between a neighbor and the target. In this study, we propose a novel PPIs prediction model AttCNNPPISP, which combines attention mechanism and convolutional neural networks (CNNs). The attention mechanism dynamically captures the pairwise correlation of each neighbor-target pair within a sliding window, and therefore makes a better understanding of the local environment of target residue. And then, CNNs take the local representation as input to make prediction. Experiments are employed on several public benchmark datasets. Compared with the state-of-the-art models, AttCNNPPISP improves the prediction performance. Also, the experimental results demonstrate that the attention mechanism is effective in terms of constructing comprehensive context information of target residue.

Spatom: a graph neural network for structure-based protein-protein interaction site prediction.

Accurate identification of protein-protein interaction (PPI) sites remains a computational challenge. We propose Spatom, a novel framework for PPI site prediction. This framework first defines a weighted digraph for a protein structure to precisely characterize the spatial contacts of residues, then performs a weighted digraph convolution to aggregate both spatial local and global information and finally adds an improved graph attention layer to drive the predicted sites to form more continuous region(s). Spatom was tested on a diverse set of challenging protein-protein complexes and demonstrated the best performance among all the compared methods. Furthermore, when tested on multiple popular proteins in a case study, Spatom clearly identifies the interaction interfaces and captures the majority of hotspots. Spatom is expected to contribute to the understanding of protein interactions and drug designs targeting protein binding.

DeepSG2PPI: A Protein-Protein Interaction Prediction Method Based on Deep Learning.

Protein-protein interaction (PPI) plays an important role in almost all life activities. Many protein interaction sites have been confirmed by biological experiments, but these PPI site identification methods are time-consuming and expensive. In this study, a deep learning-based PPI prediction method, named DeepSG2PPI, is developed. Firstly, the protein sequence information is retrieved and the local context information of each amino acid residue is calculated. A two-dimensional convolutional neural network (2D-CNN) model is employed to extract features from a two-channel coding structure, in which an attention mechanism is embedded to assign higher weights to key features. Secondly, the global statistical information of each amino acid residue and the relationship graph between the protein and GO (Gene Ontology) function annotation are built, and the graph embedding vector is constructed to represent the biological features of the protein. Finally, a 2D-CNN model and two 1D-CNN models are combined for PPI prediction. The comparison analysis with existing algorithms shows that the DeepSG2PPI method has better performance. It provides more accurate and effective PPI site prediction, which will be helpful in reducing the cost and failure rate of biological experiments.

Improving protein-protein interaction site prediction using deep residual neural network

Accurate identification of protein-protein interaction (PPI) sites is significantly important for understanding the mechanism of life and developing new drugs. However, it is expensive and time-consuming to identify PPI sites using wet-lab experiments. Developing computational methods is a new road to identify PPI sites, which can accelerate the procedure of PPI-related research. In this study, we propose a novel deep learning-based method (called D-PPIsite) to improve the accuracy of sequence-based PPI site prediction. In D-PPIsite, four discriminative sequence-driven features, i.e., position specific scoring matrix, relative solvent accessibility, position information and physical properties, are employed to feed into a well-designed deep learning module, consisting of convolutional, squeeze and excitation, and fully connected layers, to learn a prediction model. To reduce the risk of a single prediction model getting stuck in local optima, multiple prediction models with different initialization parameters are selected and integrated into one final model using the mean ensemble strategy. Experimental results on five independent testing data sets demonstrate that the proposed D-PPIsite can achieve an average accuracy of 80.2% and precision of 36.9%, covering 53.5% of all PPI sites while achieving the average Matthews correlation coefficient value (0.330) that is significantly higher than most of existing state-of-the-art prediction methods. We implement a new standalone-version predictor for predicting PPI sites, which is freely available at https://github.com/MingDongup/D-PPIsite for academic use.

A Transformer-Based Ensemble Framework for the Prediction of Protein-Protein Interaction Sites.

The identification of protein-protein interaction (PPI) sites is essential in the research of protein function and the discovery of new drugs. So far, a variety of computational tools based on machine learning have been developed to accelerate the identification of PPI sites. However, existing methods suffer from the low predictive accuracy or the limited scope of application. Specifically, some methods learned only global or local sequential features, leading to low predictive accuracy, while others achieved improved performance by extracting residue interactions from structures but were limited in their application scope for the serious dependence on precise structure information. There is an urgent need to develop a method that integrates comprehensive information to realize proteome-wide accurate profiling of PPI sites. Herein, a novel ensemble framework for PPI sites prediction, EnsemPPIS, was therefore proposed based on transformer and gated convolutional networks. EnsemPPIS can effectively capture not only global and local patterns but also residue interactions. Specifically, EnsemPPIS was unique in (a) extracting residue interactions from protein sequences with transformer and (b) further integrating global and local sequential features with the ensemble learning strategy. Compared with various existing methods, EnsemPPIS exhibited either superior performance or broader applicability on multiple PPI sites prediction tasks. Moreover, pattern analysis based on the interpretability of EnsemPPIS demonstrated that EnsemPPIS was fully capable of learning residue interactions within the local structure of PPI sites using only sequence information. The web server of EnsemPPIS is freely available at http://idrblab.org/ensemppis.

DockNet: High Throughput Protein-Protein Interface Contact Prediction.

Over 300,000 protein-protein interaction pairs have been identified in the human proteome and targeting these is fast becoming the next frontier in drug design. Predicting protein-protein interaction sites, however, is a challenging task that traditionally requires computationally expensive and time-consuming docking simulations. A major weakness of modern protein docking algorithms is the inability to account for protein flexibility, which ultimately leads to relatively poor results. Here we propose DockNet, an efficient Siamese graph-based neural network method which predicts contact residues between two interacting proteins. Unlike other methods that only utilize a protein's surface or treat the protein structure as a rigid body, DockNet incorporates the entire protein structure and places no limits on protein flexibility during an interaction. Predictions are modelled at the residue level, based on a diverse set of input node features including residue type, surface accessibility, residue depth, secondary structure, pharmacophore and torsional angles. DockNet is comparable to current state-of-the-art methods, achieving AUC value of up to 0.84 on an independent test set (DB5), can be applied to a variety of different protein structures and can be utilized in situations where accurate unbound protein structures cannot be obtained. DockNet is available at https://github.com/npwilliams09/docknet and an easy-to-use webserver at https://biosig.lab.uq.edu.au/docknet. Supplementary data are available at Bioinformatics online.

HN-PPISP: a hybrid network based on MLP-Mixer for protein-protein interaction site prediction.

Biological experimental approaches to protein-protein interaction (PPI) site prediction are critical for understanding the mechanisms of biochemical processes but are time-consuming and laborious. With the development of Deep Learning (DL) techniques, the most popular Convolutional Neural Networks (CNN)-based methods have been proposed to address these problems. Although significant progress has been made, these methods still have limitations in encoding the characteristics of each amino acid in protein sequences. Current methods cannot efficiently explore the nature of Position Specific Scoring Matrix (PSSM), secondary structure and raw protein sequences by processing them all together. For PPI site prediction, how to effectively model the PPI context with attention to prediction remains an open problem. In addition, the long-distance dependencies of PPI features are important, which is very challenging for many CNN-based methods because the innate ability of CNN is difficult to outperform auto-regressive models like Transformers. To effectively mine the properties of PPI features, a novel hybrid neural network named HN-PPISP is proposed, which integrates a Multi-layer Perceptron Mixer (MLP-Mixer) module for local feature extraction and a two-stage multi-branch module for global feature capture. The model merits Transformer, TextCNN and Bi-LSTM as a powerful alternative for PPI site prediction. On the one hand, this is the first application of an advanced Transformer (i.e. MLP-Mixer) with a hybrid network for sequence-based PPI prediction. On the other hand, unlike existing methods that treat global features altogether, the proposed two-stage multi-branch hybrid module firstly assigns different attention scores to the input features and then encodes the feature through different branch modules. In the first stage, different improved attention modules are hybridized to extract features from the raw protein sequences, secondary structure and PSSM, respectively. In the second stage, a multi-branch network is designed to aggregate information from both branches in parallel. The two branches encode the features and extract dependencies through several operations such as TextCNN, Bi-LSTM and different activation functions. Experimental results on real-world public datasets show that our model consistently achieves state-of-the-art performance over seven remarkable baselines. The source code of HN-PPISP model is available at https://github.com/ylxu05/HN-PPISP.

SENSDeep: An Ensemble Deep Learning Method for Protein-Protein Interaction Sites Prediction.

The determination of which amino acid in a protein interacts with other proteins is important in understanding the functional mechanism of that protein. Although there are experimental methods to detect protein-protein interaction sites (PPISs), these are costly, time-consuming, and require expertise. Therefore, many computational methods have been proposed to accelerate this type of research, but they are generally insufficient to predict PPISs accurately. There is a need for development in this field. In this study, we introduce a new PPISs prediction method. This method is a sequence-based Stacking ENSemble Deep (SENSDeep) learning method that has an ensemble learning model including the models of RNN, CNN, GRU sequence to sequence (GRUs2s), GRU sequence to sequence with an attention layer (GRUs2satt) and a multilayer perceptron. Two embedded features, secondary structure, and protein sequence information are added to the training data set in addition to twelve existing features to improve the prediction performance of the method. SENSDeep trained on the training data set without two extra features obtains a better performance on some of the independent testing data sets than that of the other methods in the literature, especially on scoring metrics of sensitivity, F1, MCC, and AUPRC, having increments up to 63.5%, 19.3%, 18.5%, 11.4%, respectively. It is shown that the added extra features improve the performance of the method by having almost the same performance with less data as the method trained on the data set without these added features. On the other hand, different sizes of the sliding window are tried on the data sets and an optimal sliding window size for SENSDeep is found. Moreover, SENSDeep has also been compared to structure-based methods. Some of these methods have been found to perform better. Using SENSDeep obtained by training with both training data sets, PPISs prediction examples of various proteins that are not in these training data sets are also presented. Furthermore, execution times for SENSDeep and its submodels are shown. https://github.com/enginaybey/SENSDeep.

Prediction of Protein-Protein Interaction Sites by Multifeature Fusion and RF with mRMR and IFS.

Prediction of protein-protein interaction (PPI) sites is one of the most perplexing problems in drug discovery and computational biology. Although significant progress has been made by combining different machine learning techniques with a variety of distinct characteristics, the problem still remains unresolved. In this study, a technique for PPI sites is presented using a random forest (RF) algorithm followed by the minimum redundancy maximal relevance (mRMR) approach, and the method of incremental feature selection (IFS). Physicochemical properties of proteins and the features of the residual disorder, sequence conservation, secondary structure, and solvent accessibility are incorporated. Five 3D structural characteristics are also used to predict PPI sites. Analysis of features shows that 3D structural features such as relative solvent-accessible surface area (RASA) and surface curvature (SC) help in the prediction of PPI sites. Results show that the performance of the proposed predictor is superior to several other state-of-the-art predictors, whose average prediction accuracy is 81.44%, sensitivity is 82.17%, and specificity is 80.71%, respectively. The proposed predictor is expected to become a helpful tool for finding PPI sites, and the feature analysis presented in this study will give useful insights into protein interaction mechanisms.

Prediction of protein-protein interaction sites in intrinsically disordered proteins.

Intrinsically disordered proteins (IDPs) participate in many biological processes by interacting with other proteins, including the regulation of transcription, translation, and the cell cycle. With the increasing amount of disorder sequence data available, it is thus crucial to identify the IDP binding sites for functional annotation of these proteins. Over the decades, many computational approaches have been developed to predict protein-protein binding sites of IDP (IDP-PPIS) based on protein sequence information. Moreover, there are new IDP-PPIS predictors developed every year with the rapid development of artificial intelligence. It is thus necessary to provide an up-to-date overview of these methods in this field. In this paper, we collected 30 representative predictors published recently and summarized the databases, features and algorithms. We described the procedure how the features were generated based on public data and used for the prediction of IDP-PPIS, along with the methods to generate the feature representations. All the predictors were divided into three categories: scoring functions, machine learning-based prediction, and consensus approaches. For each category, we described the details of algorithms and their performances. Hopefully, our manuscript will not only provide a full picture of the status quo of IDP binding prediction, but also a guide for selecting different methods. More importantly, it will shed light on the inspirations for future development trends and principles.

Self-Supervised Pre-training for Protein Embeddings Using Tertiary Structures

The protein tertiary structure largely determines its interaction with other molecules. Despite its importance in various structure-related tasks, fully-supervised data are often time-consuming and costly to obtain. Existing pre-training models mostly focus on amino-acid sequences or multiple sequence alignments, while the structural information is not yet exploited. In this paper, we propose a self-supervised pre-training model for learning structure embeddings from protein tertiary structures. Native protein structures are perturbed with random noise, and the pre-training model aims at estimating gradients over perturbed 3D structures. Specifically, we adopt SE(3)-invariant features as model inputs and reconstruct gradients over 3D coordinates with SE(3)-equivariance preserved. Such paradigm avoids the usage of sophisticated SE(3)-equivariant models, and dramatically improves the computational efficiency of pre-training models. We demonstrate the effectiveness of our pre-training model on two downstream tasks, protein structure quality assessment (QA) and protein-protein interaction (PPI) site prediction. Hierarchical structure embeddings are extracted to enhance corresponding prediction models. Extensive experiments indicate that such structure embeddings consistently improve the prediction accuracy for both downstream tasks.

CtP2ISP: Protein-Protein Interaction Sites Prediction Using Convolution and Transformer With Data Augmentation.

Protein-protein interactions are the basis of many cellular biological processes, such as cellular organization, signal transduction, and immune response. Identifying protein-protein interaction sites is essential for understanding the mechanisms of various biological processes, disease development, and drug design. However, it remains a challenging task to make accurate predictions, as the small amount of training data and severe imbalanced classification reduce the performance of computational methods. We design a deep learning method named ctP2ISP to improve the prediction of protein-protein interaction sites. ctP2ISP employs Convolution and Transformer to extract information and enhance information perception so that semantic features can be mined to identify protein-protein interaction sites. A weighting loss function with different sample weights is designed to suppress the preference of the model toward multi-category prediction. To efficiently reuse the information in the training set, a preprocessing of data augmentation with an improved sample-oriented sampling strategy is applied. The trained ctP2ISP was evaluated against current state-of-the-art methods on six public datasets. The results show that ctP2ISP outperforms all other competing methods on the balance metrics: F1, MCC, and AUPRC. In particular, our prediction on open tests related to viruses may also be consistent with biological insights. The source code and data can be obtained from https://github.com/lennylv/ctP2ISP.

Prediction of protein-protein interaction sites through eXtreme gradient boosting with kernel principal component analysis

Predicting protein-protein interaction sites (PPI sites) can provide important clues for understanding biological activity. Using machine learning to predict PPI sites can mitigate the cost of running expensive and time-consuming biological experiments. Here we propose PPISP-XGBoost, a novel PPI sites prediction method based on eXtreme gradient boosting (XGBoost). First, the characteristic information of protein is extracted through the pseudo-position specific scoring matrix (PsePSSM), pseudo-amino acid composition (PseAAC), hydropathy index and solvent accessible surface area (ASA) under the sliding window. Next, these raw features are preprocessed to obtain more optimal representations in order to achieve better prediction. In particular, the synthetic minority oversampling technique (SMOTE) is used to circumvent class imbalance, and the kernel principal component analysis (KPCA) is applied to remove redundant characteristics. Finally, these optimal features are fed to the XGBoost classifier to identify PPI sites. Using PPISP-XGBoost, the prediction accuracy on the training dataset Dset186 reaches 85.4%, and the accuracy on the independent validation datasets Dtestset72, PDBtestset164, Dset_448 and Dset_355 reaches 85.3%, 83.9%, 85.8% and 85.4%, respectively, which all show an increase in accuracy against existing PPI sites prediction methods. These results demonstrate that the PPISP-XGBoost method can further enhance the prediction of PPI sites.

Marker residue types at the structural regions of transmembrane alpha-helical and beta-barrel interfaces.

Membrane proteins play a variety of biological functions to the survival of organisms and functionalities of these proteins are often due to their homo- or hetero-complexation. Encoded by ~30% of the genome in most organisms, they represent the target of over half of nowadays drugs. Spanning the entirety of the cell membrane, transmembrane proteins are the most common type of membrane proteins and can be classified by secondary structures: alpha-helical and beta-barrel structures. Protein-protein interaction (PPI) have been widely studied for globular proteins and many computational tools are available for predicting PPI sites and construct models of complexes. Here, the structural regions of a non-redundant set of 232 alpha-helical and 37 beta-barrel transmembrane complexes and their interfaces are analyzed. Using the residue composition, frequency and propensity, this study brings the light on the marker residue types located at the structural regions of alpha-helical and beta-barrel transmembrane homomeric protein complexes and of their interfaces. This study also shows the necessity to relate the frequency to the composition into a ratio for immediately figuring out residue types presenting high frequencies at the interface and/or at one of its structural regions despite being a minor contributor compared to other residue types to that location's residue composition.

Deep Learning for Protein-Protein Interaction Site Prediction.

Protein-protein interactions (PPIs) are central to cellular functions. Experimental methods for predicting PPIs are well developed but are time and resource expensive and suffer from high false-positive error rates at scale. Computational prediction of PPIs is highly desirable for a mechanistic understanding of cellular processes and offers the potential to identify highly selective drug targets. In this chapter, details of developing a deep learning approach to predicting which residues in a protein are involved in forming a PPI-a task known as PPI site prediction-are outlined. The key decisions to be made in defining a supervised machine learning project in this domain are here highlighted. Alternative training regimes for deep learning models to address shortcomings in existing approaches and provide starting points for further research are discussed. This chapter is written to serve as a companion to developing deep learning approaches to protein-protein interaction site prediction, and an introduction to developing geometric deep learning projects operating on protein structure graphs.

Protein-Protein Interaction Sites Prediction Based on an Under-Sampling Strategy and Random Forest Algorithm.

The computational methods of protein-protein interaction sites prediction can effectively avoid the shortcomings of high cost and time in traditional experimental approaches. However, the serious class imbalance between interface and non-interface residues on the protein sequences limits the prediction performance of these methods. This work therefore proposed a new strategy, NearMiss-based under-sampling for unbalancing datasets and Random Forest classification (NM-RF), to predict protein interaction sites. Herein, the residues on protein sequences were represented by the PSSM-derived features, hydropathy index (HI) and relative solvent accessibility (RSA). In order to resolve the class imbalance problem, an under-sampling method based on NearMiss algorithm is adopted to remove some non-interface residues, and then the random forest algorithm is used to perform binary classification on the balanced feature datasets. Experiments show that the accuracy of NM-RF model reaches 87.6% and 84.3% on Dtestset72 and PDBtestset164 respectively, which demonstrate the effectiveness of the proposed NM-RF method in differentiating the interface or non-interface residues.

Modified naive Bayes classifier for classification of protein-protein interaction sites

The prediction of protein-protein interaction sites (PPIs) is a vital importance in biology for understanding the physical and functional interactions between molecules in living systems. There are several classification approaches for the prediction of PPI sites; the naïve Bayes classifier is one of the most popular candidates. But the ordinary naïve Bayes classifier is sensitive to unusual protein sequence profiling feature dataset and sometimes it gives ambiguous prediction results. To overcome this problem we have been modified the naïve Bayes classifier by radial basis function (RBF) kernel for the prediction of PPI sites. We investigate the performance of our proposed method compared with the popular classifiers like linear discriminant analysis (LDA), naïve Bayes classifier (NBC), support vector machine (SVM), AdaBoost and k-nearest neighbor (KNN) by the protein sequence profiling data analysis. The mNBC method showed sensitivity (86%), specificity (81%), accuracy (83%) and MCC (65%) for prediction of PPI sites.

Developing Computational Model to Predict Protein-Protein Interaction Sites Based on the XGBoost Algorithm.

The study of protein-protein interaction is of great biological significance, and the prediction of protein-protein interaction sites can promote the understanding of cell biological activity and will be helpful for drug development. However, uneven distribution between interaction and non-interaction sites is common because only a small number of protein interactions have been confirmed by experimental techniques, which greatly affects the predictive capability of computational methods. In this work, two imbalanced data processing strategies based on XGBoost algorithm were proposed to re-balance the original dataset from inherent relationship between positive and negative samples for the prediction of protein-protein interaction sites. Herein, a feature extraction method was applied to represent the protein interaction sites based on evolutionary conservatism of proteins, and the influence of overlapping regions of positive and negative samples was considered in prediction performance. Our method showed good prediction performance, such as prediction accuracy of 0.807 and MCC of 0.614, on an original dataset with 10,455 surface residues but only 2297 interface residues. Experimental results demonstrated the effectiveness of our XGBoost-based method.

Prediction of Protein-Protein Interaction Sites Using Convolutional Neural Network and Improved Data Sets.

Protein–protein interaction (PPI) sites play a key role in the formation of protein complexes, which is the basis of a variety of biological processes. Experimental methods to solve PPI sites are expensive and time-consuming, which has led to the development of different kinds of prediction algorithms. We propose a convolutional neural network for PPI site prediction and use residue binding propensity to improve the positive samples. Our method obtains a remarkable result of the area under the curve (AUC) = 0.912 on the improved data set. In addition, it yields much better results on samples with high binding propensity than on randomly selected samples. This suggests that there are considerable false-positive PPI sites in the positive samples defined by the distance between residue atoms.