Prediction Of Peptide Binding Affinity Research Articles

Deep learning pan‐specific model for interpretable MHC‐I peptide binding prediction with improved attention mechanism

Accurate prediction of peptide binding affinity to the major histocompatibility complex (MHC) proteins has the potential to design better therapeutic vaccines. Previous work has shown that pan-specific prediction algorithms can achieve better prediction performance than other approaches. However, most of the top algorithms are neural networks based black box models. Here, we propose DeepAttentionPan, an improved pan-specific model, based on convolutional neural networks and attention mechanisms for more flexible, stable and interpretable MHC-I binding prediction. With the attention mechanism, our ensemble model consisting of 20 trained networks achieves high and more stabilized prediction performance. Extensive tests on IEDB's weekly benchmark dataset show that our method achieves state-of-the-art prediction performance on 21 test allele datasets. Analysis of the peptide positional attention weights learned by our model demonstrates its capability to capture critical binding positions of the peptides, which leads to mechanistic understanding of MHC-peptide binding with high alignment with experimentally verified results. Furthermore, we show that with transfer learning, our pan model can be fine-tuned for alleles with few samples to achieve additional performance improvement. DeepAttentionPan is freely available as an open-source software at https://github.com/jjin49/DeepAttentionPan. This article is protected by copyright. All rights reserved.

Overlapping Clusters and Support Vector Machines Based Interval Type-2 Fuzzy System for the Prediction of Peptide Binding Affinity

In the post-genome era, it is becoming more complex to process high dimensional, low-instance available, and nonlinear biological datasets. This paper aims to address these characteristics as they have adverse effects on the performance of predictive models in bioinformatics. In this paper, an interval type-2 Takagi Sugeno fuzzy predictive model is proposed in order to manage high-dimensionality and nonlinearity of such datasets which is the common feature in bioinformatics. A new clustering framework is proposed for this purpose to simplify antecedent operations for an interval type-2 fuzzy system. This new clustering framework is based on overlapping regions between the clusters. The cluster analysis of partitions and statistical information derived from them has identified the upper and lower membership functions forming the premise part. This is further enhanced by adapting the regression version of support vector machines in the consequent part. The proposed method is used in experiments to quantitatively predict affinities of peptide bindings to biomolecules. This case study imposes a challenge in post-genome studies and remains an open problem due to the complexity of the biological system, diversity of peptides, and curse of dimensionality of amino acid index representation characterizing the peptides. Utilizing four different peptide binding affinity datasets, the proposed method resulted in better generalization ability for all of them yielding an improved prediction accuracy of up to 58.2% on unseen peptides in comparison with the predictive methods presented in the literature. Source code of the algorithm is available at https://github.com/sekerbigdatalab .

Quantitative prediction of peptide binding affinity by using hybrid fuzzy support vector regression

Support vector machines have a wide use for the prediction problems in life sciences. It has been shown to offer more generalisation ability in input–output mapping. However, the performance of predictive models is often negatively influenced due to the complex, high-dimensional, and non-linear nature of the post-genome data. Soft computing methods can be used to model such non-linear systems. Fuzzy systems are one of the widely used methods of soft computing that model uncertainties. It is formed of interpretable rules aiding one to gain insight into applied model. This study is therefore concerned to provide more interpretable and efficient biological model with the development of a hybrid method that integrates the fuzzy system and support vector regression. In order to demonstrate the robustness of this new hybrid method, it is applied to the prediction of peptide binding affinity being one of the most challenging problems in the post-genomic era due to diversity in peptide families and complexity and high-dimensionality in the characteristic features of the peptides. Having used four different case studies, this hybrid predictive model has yielded the highest predictive power in all the four cases and achieved an improvement of as much as 34% compared to the results presented in the literature. Availability: Matlab scripts are available at https://github.com/sekerbigdatalab/tsksvr.

Gaussian Process: A Promising Approach for the Modeling and Prediction of Peptide Binding Affinity to MHC Proteins

On the basis of Bayesian probabilistic inference, Gaussian process (GP) is a powerful machine learning method for nonlinear classification and regression, but has only very limited applications in the new areas of computational vaccinology and immunoinformatics. In the current work, we present a paradigmatic study of using GP regression technique to quantitatively model and predict the binding affinities of over 7000 immunodominant peptide epitopes to six types of human major histocompatibility complex (MHC) proteins. In this procedure, the sequence patterns of diverse peptides are characterized quantitatively and the resulting variables are then correlated with the experimentally measured affinities between different MHC and their peptide ligands, by using a linearity- and nonlinearity-hybrid GP approach. We also make systematical comparisons between the GP and two sophisticated modeling methods as partial least square (PLS) regression and support vector machine (SVM) with respect to their fitting ability, predictive power and generalization capability. The results suggest that GP could be a new and effective tool for the modeling and prediction of MHC-peptide interactions and would be promising in the field of computer-aided vaccine design (CAVD).

Quantitative prediction of MHC-II binding affinity using particle swarm optimization

Helper T-cell epitopes (Th epitopes) are the basic units which activate helper T-cell's immune response, and they are helpful for understanding the immune mechanism and developing vaccines. Peptide and major histocompatibility complex class II (MHC-II) binding is an important prerequisite event for helper T-cell immune response, and the binding peptides are usually recognized as Th epitopes, therefore we can identify Th epitopes by predicting MHC-II binding peptides. Recently, instead of differentiating the peptides as binder or non-binder, researchers are more interested in predicting binding affinities between MHC-II molecules and peptides. Motivated by the collective search strategy of the particle swarm optimization algorithm (PSO), a method was developed to make the direct prediction of peptide binding affinity. In our paper, PSO was utilized to search for the optimal position-specific scoring matrices (PSSM) from the experimentally derived allele-related peptides, and then the prediction models were constructed based on the matrices. Moreover, we evaluated several factors influencing the binding affinity, including peptide length and flanking residue length, and incorporated them into our models. The performance of our models was evaluated on three MHC-II alleles from AntiJen database and 14 MHC-II alleles from IEDB database. When compared to the existing popular quantitative methods such as MHCPred, SVRMHC, ARB and SMM-align, our method can give out better performance in terms of correlation coefficient (r) and area under ROC curve (AUC). In addition, the results demonstrated that the performance of models was further improved by incorporating the global length information, achieving average AUC value of 0.7534 and average r value of 0.4707. Quantitative prediction of MHC-II binding affinity can be modeled as an optimization problem. Our PSO based method can find the optimal PSSM, which will then be used for identifying the binding cores and scoring the binding affinities of the peptides. The experiment results show that our method is promising for the prediction of MHC-II binding affinity.

Strength in numbers: achieving greater accuracy in MHC-I binding prediction by combining the results from multiple prediction tools

BackgroundPeptides derived from endogenous antigens can bind to MHC class I molecules. Those which bind with high affinity can invoke a CD8+ immune response, resulting in the destruction of infected cells. Much work in immunoinformatics has involved the algorithmic prediction of peptide binding affinity to various MHC-I alleles. A number of tools for MHC-I binding prediction have been developed, many of which are available on the web.ResultsWe hypothesize that peptides predicted by a number of tools are more likely to bind than those predicted by just one tool, and that the likelihood of a particular peptide being a binder is related to the number of tools that predict it, as well as the accuracy of those tools. To this end, we have built and tested a heuristic-based method of making MHC-binding predictions by combining the results from multiple tools. The predictive performance of each individual tool is first ascertained. These performance data are used to derive weights such that the predictions of tools with better accuracy are given greater credence. The combined tool was evaluated using ten-fold cross-validation and was found to signicantly outperform the individual tools when a high specificity threshold is used. It performs comparably well to the best-performing individual tools at lower specificity thresholds. Finally, it also outperforms the combination of the tools resulting from linear discriminant analysis.ConclusionA heuristic-based method of combining the results of the individual tools better facilitates the scanning of large proteomes for potential epitopes, yielding more actual high-affinity binders while reporting very few false positives.

In Silico Prediction of Peptide Binding Affinity to Class I Mouse Major Histocompatibility Complexes: A Comparative Molecular Similarity Index Analysis (CoMSIA) Study

Current methods for the in silico identification of T cell epitopes (which form the basis of many vaccines, diagnostics, and reagents) rely on the accurate prediction of peptide-major histocompatibility complex (MHC) affinity. A three-dimensional quantitative structure-activity relationship (3D-QSAR) for the prediction of peptide binding to class I MHC molecules was established using the comparative molecular similarity index analysis (CoMSIA) method. Three MHC alleles were studied: H2-D(b), H2-K(b), and H2-K(k). Models were produced for each allele. Each model consisted of five physicochemical descriptors-steric bulk, electrostatic potentials, hydrophobic interactions, and hydrogen-bond donor and hydrogen-bond acceptor abilities. The models have an acceptable level of predictivity: cross-validation leave-one-out statistical terms q2 and SEP (standard error of prediction) ranged between 0.490 and 0.679 and between 0.525 and 0.889, respectively. The non-cross-validated statistical terms r2 and SEE (standard error of estimate) ranged between 0.913 and 0.979 and between 0.167 and 0.248, respectively. The use of coefficient contour maps, which indicate favored and disfavored areas for each position of the MHC-bound peptides, allowed the binding specificity of each allele to be identified, visualized, and understood. The present study demonstrates the effectiveness of CoMSIA as a method for studying peptide-MHC interactions. The peptides used in this study are available on the Internet (http://www.jenner.ac.uk/AntiJen). The partial least-squares method is available commercially in the SYBYL molecular modeling software package.

O495 - A strategy for prediction of peptide binding affinity for the human peptide transporter

O495 - A strategy for prediction of peptide binding affinity for the human peptide transporter