DeepPRObind: Modular Deep Learner that Accurately Predicts Structure and Disorder-Annotated Protein Binding Residues

Current sequence-based predictors of protein-binding residues (PBRs) belong to two distinct categories: structure-trained vs. intrinsic disorder-trained. Since disordered PBRs differ from structured PBRs in several ways, including ability to bind multiple partners by folding into different conformations and enrichment in different amino acids, the structure-trained and disorder-trained predictors were shown to provide inaccurate results for the other annotation type. A simple consensus-based solution that combines structure- and disorder-trained methods provides limited levels of predictive performance and generates relatively many cross-predictions, where residues that interact with other ligand types are predicted as PBRs. We address this unsolved problem by designing a novel and fast deep-learner, DeepPRObind, that relies on carefully designed modular convolutional architecture and uses innovative aggregate input features. Comparative empirical tests on a low-similarity test dataset reveal that DeepPRObind generates accurate predictions of structured and disordered PBRs and low amounts of cross-predictions, outperforming a comprehensive collection of 12 predictors of PBRs. Given the relatively low runtime of DeepPRObind (40 seconds per protein), we further validate its results based on an analysis of putative PBRs in the yeast proteome, confirming that interactions in disordered regions are enriched among hub proteins. We release DeepPRObind as a convenient web server at https://www.csuligroup.com/DeepPRObind/. (C) 2023 Elsevier Ltd. All rights reserved.