Efficient Generation of Protein Pockets with PocketGen.

Designing protein-binding proteins plays an important role in drug discovery. However, AI-based design of such proteins is challenging due to complex ligand-protein interactions, flexibility of ligand molecules and amino acid side chains, and sequence-structure dependencies. We introduce PocketGen, a deep generative model that produces both the residue sequence and atom structure of the protein regions where interactions with ligand molecules occur. PocketGen ensures sequence-structure consistency by using a graph transformer for structural encoding and a sequence refinement module based on a protein language model. The bilevel graph transformer captures interactions at multiple granularities across atom, residue, and ligand levels. To enhance sequence refinement, PocketGen integrates a structural adapter with the protein language model, ensuring consistency between structure-based and sequence-based predictions. Results show that PocketGen can generate high-fidelity protein pockets with superior binding affinity and structural validity. It is ten times faster than physics-based methods and achieves a 95% success rate, defined as the percentage of generated pockets with higher binding affinity than reference pockets, along with achieving an amino acid recovery rate exceeding 64%.