MOTIVATION: Understanding the mechanisms and structural mappings between molecules and pathway classes are critical for design of reaction predictors for synthesizing new molecules. This article studies the problem of prediction of classes of metabolic pathways (series of chemical reactions occurring within a cell) in which a given biochemical compound participates. We apply a hybrid machine learning approach consisting of graph convolutional networks used to extract molecular shape features as input to a random forest classifier. In contrast to previously applied machine learning methods for this problem, our framework automatically extracts relevant shape features directly from input SMILES representations, which are atom-bond specifications of chemical structures composing the molecules. RESULTS: Our method is capable of correctly predicting the respective metabolic pathway class of 95.16% of tested compounds, whereas competing methods only achieve an accuracy of 84.92% or less. Furthermore, our framework extends to the task of classification of compounds having mixed membership in multiple pathway classes. Our prediction accuracy for this multi-label task is 95.62%. We analyze the relative importance of various global physicochemical features to the pathway class prediction problem and show that simple linear/logistic regression models can predict the values of these global features from the shape features extracted using our framework. AVAILABILITY AND IMPLEMENTATION: https://github.com/baranwa2/MetabolicPathwayPrediction.

BACKGROUND: Development of new methods for analysis of protein-protein interactions (PPIs) at molecular and nanometer scales gives insights into intracellular signaling pathways and will improve understanding of protein functions, as well as other nanoscale structures of biological and abiological origins. Recent advances in computational tools, particularly the ones involving modern deep learning algorithms, have been shown to complement experimental approaches for describing and rationalizing PPIs. However, most of the existing works on PPI predictions use protein-sequence information, and thus have difficulties in accounting for the three-dimensional organization of the protein chains. RESULTS: In this study, we address this problem and describe a PPI analysis based on a graph attention network, named Struct2Graph, for identifying PPIs directly from the structural data of folded protein globules. Our method is capable of predicting the PPI with an accuracy of 98.89% on the balanced set consisting of an equal number of positive and negative pairs. On the unbalanced set with the ratio of 1:10 between positive and negative pairs, Struct2Graph achieves a fivefold cross validation average accuracy of 99.42%. Moreover, Struct2Graph can potentially identify residues that likely contribute to the formation of the protein-protein complex. The identification of important residues is tested for two different interaction types: (a) Proteins with multiple ligands competing for the same binding area, (b) Dynamic protein-protein adhesion interaction. Struct2Graph identifies interacting residues with 30% sensitivity, 89% specificity, and 87% accuracy. CONCLUSIONS: In this manuscript, we address the problem of prediction of PPIs using a first of its kind, 3D-structure-based graph attention network (code available at https://github.com/baranwa2/Struct2Graph ). Furthermore, the novel mutual attention mechanism provides insights into likely interaction sites through its unsupervised knowledge selection process. This study demonstrates that a relatively low-dimensional feature embedding learned from graph structures of individual proteins outperforms other modern machine learning classifiers based on global protein features. In addition, through the analysis of single amino acid variations, the attention mechanism shows preference for disease-causing residue variations over benign polymorphisms, demonstrating that it is not limited to interface residues.

MOTIVATION: Understanding the mechanisms and structural mappings between molecules and pathway classes are critical for design of reaction predictors for synthesizing new molecules. This article studies the problem of prediction of classes of metabolic pathways (series of chemical reactions occurring within a cell) in which a given biochemical compound participates. We apply a hybrid machine learning approach consisting of graph convolutional networks used to extract molecular shape features as input to a random forest classifier. In contrast to previously applied machine learning methods for this problem, our framework automatically extracts relevant shape features directly from input SMILES representations, which are atom-bond specifications of chemical structures composing the molecules. RESULTS: Our method is capable of correctly predicting the respective metabolic pathway class of 95.16% of tested compounds, whereas competing methods only achieve an accuracy of 84.92% or less. Furthermore, our framework extends to the task of classification of compounds having mixed membership in multiple pathway classes. Our prediction accuracy for this multi-label task is 97.61%. We analyze the relative importance of various global physicochemical features to the pathway class prediction problem and show that simple linear/logistic regression models can predict the values of these global features from the shape features extracted using our framework. AVAILABILITY AND IMPLEMENTATION: https://github.com/baranwa2/MetabolicPathwayPrediction. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.