{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,18]],"date-time":"2026-03-18T02:31:26Z","timestamp":1773801086143,"version":"3.50.1"},"reference-count":0,"publisher":"Association for the Advancement of Artificial Intelligence (AAAI)","issue":"2","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["AAAI"],"abstract":"<jats:p>The ability to engineer optimized protein variants has transformative potential for biotechnology and medicine. Prior sequence-based optimization methods struggle with the high-dimensional complexities due to the epistasis effect and the disregard for structural constraints. To address this, we propose HADES, a Bayesian optimization method utilizing Hamiltonian dynamics to efficiently sample from a structure-aware approximated posterior. Leveraging momentum and uncertainty in the simulated physical movements, HADES enables rapid transition of proposals toward promising areas. A position discretization procedure is introduced to propose discrete protein sequences from such continuous state system. The posterior surrogate is powered by a two-stage encoder-decoder framework to determine the structure and function relationships between mutant neighbors, consequently learning a smoothed landscape to sample from. Extensive experiments demonstrate that our method outperforms state-of-the-art baselines in in-silico evaluations across most metrics. Remarkably, our approach offers a unique advantage by leveraging the mutual constraints between protein structure and sequence, facilitating the design of protein sequences with similar structures and optimized properties.<\/jats:p>","DOI":"10.1609\/aaai.v40i2.37084","type":"journal-article","created":{"date-parts":[[2026,3,17]],"date-time":"2026-03-17T22:54:10Z","timestamp":1773788050000},"page":"1132-1140","source":"Crossref","is-referenced-by-count":0,"title":["Efficient Protein Optimization via Structure-aware Hamiltonian Dynamics"],"prefix":"10.1609","volume":"40","author":[{"given":"Jiahao","family":"Wang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shuangjia","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"9382","published-online":{"date-parts":[[2026,3,14]]},"container-title":["Proceedings of the AAAI Conference on Artificial Intelligence"],"original-title":[],"link":[{"URL":"https:\/\/ojs.aaai.org\/index.php\/AAAI\/article\/download\/37084\/41046","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/ojs.aaai.org\/index.php\/AAAI\/article\/download\/37084\/41046","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,17]],"date-time":"2026-03-17T22:54:10Z","timestamp":1773788050000},"score":1,"resource":{"primary":{"URL":"https:\/\/ojs.aaai.org\/index.php\/AAAI\/article\/view\/37084"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,14]]},"references-count":0,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2026,3,17]]}},"URL":"https:\/\/doi.org\/10.1609\/aaai.v40i2.37084","relation":{},"ISSN":["2374-3468","2159-5399"],"issn-type":[{"value":"2374-3468","type":"electronic"},{"value":"2159-5399","type":"print"}],"subject":[],"published":{"date-parts":[[2026,3,14]]}}}