MERIT: Accurate Prediction of Multi Ligand-binding Residues with Hybrid Deep Transformer Network, Evolutionary Couplings and Transfer Learning.

Multi-ligand binding residues (MLBRs) are amino acids in protein sequences that interact with multiple different ligands that include proteins, peptides, nucleic acids, and a variety of small molecules. MLBRs are implicated in a number of cellular functions and targeted in a context of multiple human diseases. There are many sequence-based predictors of residues that interact with specific ligand types and they can be collectively used to identify MLBRs. However, there are no methods that directly predict MLBRs. To this end, we conceptualize, design, evaluate and release MERIT (Multi-binding rEsidues pRedIcTor). This tool relies on a custom-crafted deep neural network that implements a number of innovative features, such as a multi-layered/step architecture with transformer modules that we train using a custom-designed loss function, computation of evolutionary couplings, and application of transfer learning. These innovations boost predictive performance, which we demonstrate using an ablation analysis. In particular, they reduce the number of cross-predictions, defined as residues that interact with a single ligand type that are incorrectly predicted as MLBRs. We compare MERIT against a representative selection of current and popular ligand-specific predictors, meta-predictors that combine their results to identify MLBRs, and a baseline regression-based predictor. These tests reveal that MERIT provides accurate predictions and statistically outperforms these alternatives. Moreover, using two test datasets, one with MLBRs and another with only the single ligand binding residues, we show that MERIT consistently produces relatively low false positive rates, including low rates of cross-predictions. The web server and datasets from this study are freely available at http://biomine.cs.vcu.edu/servers/MERIT/.