A fast protein binding site comparison algorithm for proteome-wide protein function prediction and drug repurposing

The expansion of three-dimensional protein structures and enhanced computing power have significantly facilitated our understanding of protein sequence/structure/function relationships. A challenge in structural genomics is to predict the function of uncharacterized proteins. Protein function deconvolution based on global sequence or structural homology is impracticable when a protein relates to no other proteins with known function, and in such cases, functional relationships can be established by detecting their local ligand binding site similarity. Here, we introduce a sequence order-independent comparison algorithm, PocketShape, for structural proteome-wide exploration of protein functional site by fully considering the geometry of the backbones, orientation of the sidechains, and physiochemical properties of the pocket-lining residues. PocketShape is efficient in distinguishing similar from dissimilar ligand binding site pairs by retrieving 99.3% of the similar pairs while rejecting 100% of the dissimilar pairs on a dataset containing 1538 binding site pairs. This method successfully classifies 83 enzyme structures with diverse functions into 12 clusters, which is highly in accordance with the actual structural classification of proteins classification. PocketShape also achieves superior performances than other methods in protein profiling based on experimental data. Potential new applications for representative SARS-CoV-2 drugs Remdesivir and 11a are predicted. The high accuracy and time-efficient characteristics of PocketShape will undoubtedly make it a promising complementary tool for proteome-wide protein function inference and drug repurposing study.