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However, artificial-intelligence-based design of such proteins is challenging due to the complexity of protein\u2013ligand interactions, the flexibility of ligand molecules and amino acid side chains, and sequence\u2013structure dependencies. We introduce PocketGen, a deep generative model that produces residue sequence and atomic structure of the protein regions in which ligand interactions occur. PocketGen promotes consistency between protein sequence and structure by using a graph transformer for structural encoding and a sequence refinement module based on a protein language model. The graph transformer captures interactions at multiple scales, including atom, residue and ligand levels. For sequence refinement, PocketGen integrates a structural adapter into the protein language model, ensuring that structure-based predictions align with sequence-based predictions. PocketGen can generate high-fidelity protein pockets with enhanced binding affinity and structural validity. It operates ten times faster than physics-based methods and achieves a 97% success rate, defined as the percentage of generated pockets with higher binding affinity than reference pockets. Additionally, it attains an amino acid recovery rate exceeding 63%.<\/jats:p>","DOI":"10.1038\/s42256-024-00920-9","type":"journal-article","created":{"date-parts":[[2024,11,15]],"date-time":"2024-11-15T05:02:41Z","timestamp":1731646961000},"page":"1382-1395","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Efficient generation of protein pockets with PocketGen"],"prefix":"10.1038","volume":"6","author":[{"given":"Zaixi","family":"Zhang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7114-3664","authenticated-orcid":false,"given":"Wan Xiang","family":"Shen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8530-7228","authenticated-orcid":false,"given":"Marinka","family":"Zitnik","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,11,15]]},"reference":[{"key":"920_CR1","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1038\/nature12443","volume":"501","author":"CE Tinberg","year":"2013","unstructured":"Tinberg, C. 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