Prediction Of Protein-protein Interaction Sites Research Articles

LGS-PPIS: A Local-Global Structural Information Aggregation Framework for Predicting Protein-Protein Interaction Sites.

Exploring protein-protein interaction sites (PPIS) is of significance to elucidating the intrinsic mechanisms of diverse biological processes. On this basis, recent studies have applied deep learning-based technologies to overcome the high cost of wet experiments for PPIS determination. However, the existing methods still suffer from two limitations that remain to be solved. Firstly, the process of feature aggregation in most methods only took into account node features, but ignored the complex edge features of the target residue to its neighbor residues, resulting in insufficient local feature extraction. Secondly, such feature aggregation was limited to aggregating spatially adjacent residues, and could not capture the "remote" residues that played a critical role in determining PPIS, which can be summed up as the lack of global feature at the residue level. To break the above limitations, a local-global structural information aggregation framework, LGS-PPIS, was proposed in this study, including two modules of edge-aware graph convolutional network (EA-GCN) and self-attention integrated with initial residual and identity mapping (SA-RIM), which achieved the aggregation of local and global information for PPIS prediction. Evaluation results of LGS-PPIS showed that the proposed method outperformed state-of-the-art deep learning methods on three widely used PPIS prediction benchmarks. Besides, the results of ablation experiments demonstrated that the local features from spatially adjacent residues and global features from "remote" residues separately captured by EA-GCN and SA-RIM could benefit the model performance. Among them, the former was shown to have a more significant role in the PPIS prediction.

GACT-PPIS: Prediction of protein-protein interaction sites based on graph structure and transformer network

The prediction of protein-protein interaction sites (PPIS) is currently crucial for regulating many biological activities in cells and developing drugs for various diseases. Deep learning-based methods have been proposed for predicting PPIS, significantly reducing the manpower and time costs associated with traditional experimental methods such as yeast two-hybrid, mass spectrometry, and affinity purification. However, the predictive accuracy of these deep learning methods has not yet reached the expected level. Therefore, we introduce a model called GACT-PPIS.The design of the GACT-PPIS algorithm aims to utilize combined information from protein sequences and structures as input to predict protein-protein interaction sites. The core of GACT-PPIS utilizes an Enhanced Graph Attention Network (EGAT) with initial residual and identity mappings, along with a deep Transformer network as the basic units, supplemented by Graph Convolutional Networks (GCN), effectively aggregating information from neighboring nodes for each node. After multiple network layers, the information of the entire protein is also fused into the nodes, and the Transformer network further enhances the model's performance.Experimental results show that GACT-PPIS outperforms the most representative models in terms of Recall, F1-measure, MCC, AUROC, and AUPRC on the benchmark test set (Test-60). Additionally, on other independent test sets (UBTest-31-6), GACT-PPIS leads in terms of Accuracy, Precision, Recall, F1-measure, MCC, AUROC, and AUPRC compared to the most representative models. It is worth noting that GACT-PPIS demonstrates excellent generalization and versatility across different test sets, showcasing good performance on multiple test sets for the same trained GACT-PPIS model.

Pair-EGRET: Enhancing the prediction of protein-protein interaction sites through graph attention networks and protein language models.

Proteins are responsible for most biological functions, many of which require the interaction of more than one protein molecule. However, accurately predicting protein-protein interaction (PPI) sites (the interfacial residues of a protein that interact with other protein molecules) remains a challenge. The growing demand and cost associated with the reliable identification of PPI sites using conventional experimental methods call for computational tools for automated prediction and understanding of PPIs. We present Pair-EGRET, an edge-aggregated graph attention network that leverages the features extracted from pre-trained transformer-like models to accurately predict PPI sites. Pair-EGRET works on a k-nearest neighbor graph, representing the three-dimensional structure of a protein, and utilizes the cross-attention mechanism for accurate identification of interfacial residues of a pair of proteins. Through an extensive evaluation study using a diverse array of experimental data, evaluation metrics, and case studies on representative protein sequences, we demonstrate that Pair-EGRET can achieve remarkable performance in predicting PPI sites. Moreover, Pair-EGRET can provide interpretable insights from the learned cross-attention matrix. Pair-EGRET is freely available in open source form at the GitHub Repository https://github.com/1705004/Pair-EGRET. Supplementary data are available at Bioinformatics online.

DGCPPISP: a PPI site prediction model based on dynamic graph convolutional network and two-stage transfer learning

BackgroundProteins play a pivotal role in the diverse array of biological processes, making the precise prediction of protein–protein interaction (PPI) sites critical to numerous disciplines including biology, medicine and pharmacy. While deep learning methods have progressively been implemented for the prediction of PPI sites within proteins, the task of enhancing their predictive performance remains an arduous challenge.ResultsIn this paper, we propose a novel PPI site prediction model (DGCPPISP) based on a dynamic graph convolutional neural network and a two-stage transfer learning strategy. Initially, we implement the transfer learning from dual perspectives, namely feature input and model training that serve to supply efficacious prior knowledge for our model. Subsequently, we construct a network designed for the second stage of training, which is built on the foundation of dynamic graph convolution.ConclusionsTo evaluate its effectiveness, the performance of the DGCPPISP model is scrutinized using two benchmark datasets. The ensuing results demonstrate that DGCPPISP outshines competing methods in terms of performance. Specifically, DGCPPISP surpasses the second-best method, EGRET, by margins of 5.9%, 10.1%, and 13.3% for F1-measure, AUPRC, and MCC metrics respectively on Dset_186_72_PDB164. Similarly, on Dset_331, it eclipses the performance of the runner-up method, HN-PPISP, by 14.5%, 19.8%, and 29.9% respectively.

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 article 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.

RGCNPPIS: A Residual Graph Convolutional Network for Protein-Protein Interaction Site Prediction.

Accurate identification of protein-protein interaction (PPI) sites is crucial for understanding the mechanisms of biological processes, developing PPI networks, and detecting protein functions. Currently, most computational methods primarily concentrate on sequence context features and rarely consider the spatial neighborhood features. To address this limitation, we propose a novel residual graph convolutional network for structure-based PPI site prediction (RGCNPPIS). Specifically, we use a GCN module to extract the global structural features from all spatial neighborhoods, and utilize the GraphSage module to extract local structural features from local spatial neighborhoods. To the best of our knowledge, this is the first work utilizing local structural features for PPI site prediction. We also propose an enhanced residual graph connection to combine the initial node representation, local structural features, and the previous GCN layer's node representation, which enables information transfer between layers and alleviates the over-smoothing problem. Evaluation results demonstrate that RGCNPPIS outperforms state-of-the-art methods on three independent test sets. In addition, the results of ablation experiments and case studies confirm that RGCNPPIS is an effective tool for PPI site prediction.

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.

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.

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.

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.

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.

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.