Proteases are enzymes that cleave and hydrolyse the peptide bonds between two specific amino acid residues of target substrate proteins. Protease -controlled proteolysis plays a key role in the degradation and recycling of proteins, which is essential for various physiological processes. Thus, solving the substrate identification problem will have important implications for the precise understanding of functions and physiological roles of proteases, as well as for therapeutic target identification and pharmaceutical applicability. Consequently, there is a great demand for bioinformatics methods that can predict novel substrate cleavage events with high accuracy by utilizing both sequence and structural information. In this study, we present Procleave, a novel bioinformatics approach for predicting protease-specific substrates and specific cleavage sites by taking into account both their sequence and 3D structural information. Structural features of known cleavage sites were represented by discrete values using a LOWESS data-smoothing optimization method, which turned out to be critical for the performance of Procleave. The optimal approximations of all structural parameter values were encoded in a conditional random field (CRF) computational framework, alongside sequence and chemical group-based features. Here, we demonstrate the outstanding performance of Procleave through extensive benchmarking and independent tests. Procleave is capable of correctly identifying most cleavage sites in the case study. Importantly, when applied to the human structural proteome encompassing 17,628 protein structures, Procleave suggests a number of potential novel target substrates and their corresponding cleavage sites of different proteases. Procleave is implemented as a webserver and is freely accessible at http://procleave.erc.monash.edu/ .
Motivation Proteases are enzymes that cleave target substrate proteins by catalyzing the hydrolysis of peptide bonds between specific amino acids. While the functional proteolysis regulated by proteases plays a central role in the ‘life and death’ cellular processes, many of the corresponding substrates and their cleavage sites were not found yet. Availability of accurate predictors of the substrates and cleavage sites would facilitate understanding of proteases’ functions and physiological roles. Deep learning is a promising approach for the development of accurate predictors of substrate cleavage events. Results We propose DeepCleave, the first deep learning-based predictor of protease-specific substrates and cleavage sites. DeepCleave uses protein substrate sequence data as input and employs convolutional neural networks with transfer learning to train accurate predictive models. High predictive performance of our models stems from the use of high-quality cleavage site features extracted from the substrate sequences through the deep learning process, and the application of transfer learning, multiple kernels and attention layer in the design of the deep network. Empirical tests against several related state-of-the-art methods demonstrate that DeepCleave outperforms these methods in predicting caspase and matrix metalloprotease substrate-cleavage sites. Availability and implementation The DeepCleave webserver and source code are freely available at http://deepcleave.erc.monash.edu/. Supplementary information Supplementary data are available at Bioinformatics online.
Linear kernel Support Vector Machine Recursive Feature Elimination (SVM-RFE) is known as an excellent feature selection algorithm. Nonlinear SVM is a black box classifier for which we do not know the mapping function explicitly. Thus, the weight vector w cannot be explicitly computed. In this paper, we proposed a feature selection algorithm utilizing Support Vector Machine with RBF kernel based on Recursive Feature Elimination (SVM-RBF-RFE), which expands nonlinear RBF kernel into its Maclaurin series, and then the weight vector w is computed from the series according to the contribution made to classification hyperplane by each feature. Using w 2 i as ranking criterion, SVM-RBF-RFE starts with all the features, and eliminates one feature with the least squared weight at each step until all the features are ranked. We use SVM and KNN classifiers to evaluate nested subsets of features selected by SVM-RBF-RFE. Experimental results based on 3 UCI and 3 microarray datasets show SVM-RBF-RFE generally performs better than information gain and SVM-RFE.
Anti-cancer peptides (ACPs) are known as potential therapeutics for cancer. Due to their unique ability to target cancer cells without affecting healthy cells directly, they have been extensively studied. Many peptide-based drugs are currently evaluated in the preclinical and clinical trials. Accurate identification of ACPs has received considerable attention in recent years; as such, a number of machine learning-based methods for in silico identification of ACPs have been developed. These methods promote the research on the mechanism of ACPs therapeutics against cancer to some extent. There is a vast difference in these methods in terms of their training/testing datasets, machine learning algorithms, feature encoding schemes, feature selection methods and evaluation strategies used. Therefore, it is desirable to summarize the advantages and disadvantages of the existing methods, provide useful insights and suggestions for the development and improvement of novel computational tools to characterize and identify ACPs. With this in mind, we firstly comprehensively investigate 16 state-of-the-art predictors for ACPs in terms of their core algorithms, feature encoding schemes, performance evaluation metrics and webserver/software usability. Then, comprehensive performance assessment is conducted to evaluate the robustness and scalability of the existing predictors using a well-prepared benchmark dataset. We provide potential strategies for the model performance improvement. Moreover, we propose a novel ensemble learning framework, termed ACPredStackL, for the accurate identification of ACPs. ACPredStackL is developed based on the stacking ensemble strategy combined with SVM, Naïve Bayesian, lightGBM and KNN. Empirical benchmarking experiments against the state-of-the-art methods demonstrate that ACPredStackL achieves a comparative performance for predicting ACPs. The webserver and source code of ACPredStackL is freely available at http://bigdata.biocie.cn/ACPredStackL/ and https://github.com/liangxiaoq/ACPredStackL, respectively.
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