PocketScope is a training-free framework that represents cavity-lining residues using frozen ESM-C 600M embeddings and retrieves related binding sites through exhaustive lateinteraction MaxSim, without pooling or approximate nearest-neighbor search.
Abstract
Protein language models (PLMs) provide powerful representations of protein sequence, but their utility for proteome-scale binding-site retrieval remains unclear. Here, we present PocketScope, a training-free framework that represents cavity-lining residues using frozen ESM-C 600M embeddings and retrieves related binding sites through exhaustive lateinteraction MaxSim, without pooling or approximate nearest-neighbor search. PocketScope identified 153,805 cavities across 37,682 proteins in the AlphaFold human proteome and recovered documented drug off-targets across a curated set of pharmacological pairs. On the ProSPECCTs benchmark, PocketScope ranks 1st of 23 methods by mean rank across the ten collections. PocketScope provides a practical framework for proteome-scale off-target prediction. PocketScope is open source and also freely available as a web server at https://www.bhargavaresearch.org/pocketscope.
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