A comprehensive review of protein-centric predictors for biomolecular interactions: from proteins to nucleic acids and beyond

Abstract

Abstract Proteins interact with diverse ligands to perform a large number of biological functions, such as gene expression and signal transduction. Accurate identification of these protein–ligand interactions is crucial to the understanding of molecular mechanisms and the development of new drugs. However, traditional biological experiments are time-consuming and expensive. With the development of high-throughput technologies, an increasing amount of protein data is available. In the past decades, many computational methods have been developed to predict protein–ligand interactions. Here, we review a comprehensive set of over 160 protein–ligand interaction predictors, which cover protein–protein, protein−nucleic acid, protein−peptide and protein−other ligands (nucleotide, heme, ion) interactions. We have carried out a comprehensive analysis of the above four types of predictors from several significant perspectives, including their inputs, feature profiles, models, availability, etc. The current methods primarily rely on protein sequences, especially utilizing evolutionary information. The significant improvement in predictions is attributed to deep learning methods. Additionally, sequence-based pretrained models and structure-based approaches are emerging as new trends.