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A compound-based computational approach for the accurate determination of hot spots.

ABSTRACT: A plethora of both experimental and computational methods have been proposed in the past 20 years for the identification of hot spots at a protein-protein interface. The experimental determination of a protein-protein complex followed by alanine scanning mutagenesis, though able to determine hot spots with much precision, is expensive and has no guarantee of success while the accuracy of the current computational methods for hot-spot identification remains low. Here, we present a novel structure-based computational approach that accurately determines hot spots through docking into a set of proteins homologous to only one of the two interacting partners of a compound capable of disrupting the protein-protein interaction (PPI). This approach has been applied to identify the hot spots of human activin receptor type II (ActRII) critical for its binding toward Cripto-I. The subsequent experimental confirmation of the computationally identified hot spots portends a potentially accurate method for hot-spot determination in silico given a compound capable of disrupting the PPI in question. The hot spots of human ActRII first reported here may well become the focal points for the design of small molecule drugs that target the PPI. The determination of their interface may have significant biological implications in that it suggests that Cripto-I plays an important role in both activin and nodal signal pathways.

SUBMITTER: Wang L

PROVIDER: S-EPMC3832042 | biostudies-literature | 2013 Aug

REPOSITORIES: biostudies-literature

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A compound-based computational approach for the accurate determination of hot spots.

Wang Lincong L Hou Yaqin Y Quan Haihua H Xu Weiwei W Bao Yongli Y Li Yuxin Y Fu Yuan Y Zou Shuxue S

Protein science : a publication of the Protein Society 20130703 8

A plethora of both experimental and computational methods have been proposed in the past 20 years for the identification of hot spots at a protein-protein interface. The experimental determination of a protein-protein complex followed by alanine scanning mutagenesis, though able to determine hot spots with much precision, is expensive and has no guarantee of success while the accuracy of the current computational methods for hot-spot identification remains low. Here, we present a novel structure ...[more]

PMID: 23776011

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Project description:BACKGROUND: It is well known that most of the binding free energy of protein interaction is contributed by a few key hot spot residues. These residues are crucial for understanding the function of proteins and studying their interactions. Experimental hot spots detection methods such as alanine scanning mutagenesis are not applicable on a large scale since they are time consuming and expensive. Therefore, reliable and efficient computational methods for identifying hot spots are greatly desired and urgently required. RESULTS: In this work, we introduce an efficient approach that uses support vector machine (SVM) to predict hot spot residues in protein interfaces. We systematically investigate a wide variety of 62 features from a combination of protein sequence and structure information. Then, to remove redundant and irrelevant features and improve the prediction performance, feature selection is employed using the F-score method. Based on the selected features, nine individual-feature based predictors are developed to identify hot spots using SVMs. Furthermore, a new ensemble classifier, namely APIS (A combined model based on Protrusion Index and Solvent accessibility), is developed to further improve the prediction accuracy. The results on two benchmark datasets, ASEdb and BID, show that this proposed method yields significantly better prediction accuracy than those previously published in the literature. In addition, we also demonstrate the predictive power of our proposed method by modelling two protein complexes: the calmodulin/myosin light chain kinase complex and the heat shock locus gene products U and V complex, which indicate that our method can identify more hot spots in these two complexes compared with other state-of-the-art methods. CONCLUSION: We have developed an accurate prediction model for hot spot residues, given the structure of a protein complex. A major contribution of this study is to propose several new features based on the protrusion index of amino acid residues, which has been shown to significantly improve the prediction performance of hot spots. Moreover, we identify a compact and useful feature subset that has an important implication for identifying hot spot residues. Our results indicate that these features are more effective than the conventional evolutionary conservation, pairwise residue potentials and other traditional features considered previously, and that the combination of our and traditional features may support the creation of a discriminative feature set for efficient prediction of hot spot residues. The data and source code are available on web site http://home.ustc.edu.cn/~jfxia/hotspot.html.

Project description:BackgroundProtein-DNA interaction governs a large number of cellular processes, and it can be altered by a small fraction of interface residues, i.e., the so-called hot spots, which account for most of the interface binding free energy. Accurate prediction of hot spots is critical to understand the principle of protein-DNA interactions. There are already some computational methods that can accurately and efficiently predict a large number of hot residues. However, the insufficiency of experimentally validated hot-spot residues in protein-DNA complexes and the low diversity of the employed features limit the performance of existing methods.ResultsHere, we report a new computational method for effectively predicting hot spots in protein-DNA binding interfaces. This method, called PreHots (the abbreviation of Predicting Hotspots), adopts an ensemble stacking classifier that integrates different machine learning classifiers to generate a robust model with 19 features selected by a sequential backward feature selection algorithm. To this end, we constructed two new and reliable datasets (one benchmark for model training and one independent dataset for validation), which totally consist of 123 hot spots and 137 non-hot spots from 89 protein-DNA complexes. The data were manually collected from the literature and existing databases with a strict process of redundancy removal. Our method achieves a sensitivity of 0.813 and an AUC score of 0.868 in 10-fold cross-validation on the benchmark dataset, and a sensitivity of 0.818 and an AUC score of 0.820 on the independent test dataset. The results show that our approach outperforms the existing ones.ConclusionsPreHots, which is based on stack ensemble of boosting algorithms, can reliably predict hot spots at the protein-DNA binding interface on a large scale. Compared with the existing methods, PreHots can achieve better prediction performance. Both the webserver of PreHots and the datasets are freely available at: http://dmb.tongji.edu.cn/tools/PreHots/ .

Dataset Information

A compound-based computational approach for the accurate determination of hot spots.

Publications

A compound-based computational approach for the accurate determination of hot spots.

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