{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T23:16:55Z","timestamp":1788218215758,"version":"build-2803163510"},"reference-count":68,"publisher":"American Chemical Society (ACS)","issue":"16","license":[{"start":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T00:00:00Z","timestamp":1786320000000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-029"},{"start":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T00:00:00Z","timestamp":1786320000000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-037"},{"start":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T00:00:00Z","timestamp":1786320000000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-045"}],"funder":[{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2024YFA0917602"],"award-info":[{"award-number":["2024YFA0917602"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012226","name":"Fundamental Research Funds for the Central Universities","doi-asserted-by":"publisher","award":["20720240124"],"award-info":[{"award-number":["20720240124"]}],"id":[{"id":"10.13039\/501100012226","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/na","name":"Scientific Research Innovation Capability Support Project for Young Faculty","doi-asserted-by":"publisher","award":["ZYGXONJSKYCXNLZCXM-B6"],"award-info":[{"award-number":["ZYGXONJSKYCXNLZCXM-B6"]}],"id":[{"id":"10.13039\/na","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,8,25]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Identifying beneficial distal mutations remains a key challenge in enzyme engineering, as such residues can regulate activity through long-range dynamical coupling and allosteric communication. Although protein language models effectively capture sequence and evolutionary information, they lack explicit representation of conformational dynamics in the presence of the substrate, limiting their ability to detect distal regulatory sites. Here, we present an integrated framework that combines molecular dynamics (MD)-derived descriptors with the zero-shot prediction model GEMS to identify beneficial distal mutations. Compared to the pure zero-shot model, MD-derived descriptors efficiently capture key distal residues involved in dynamical coupling and allosteric communication with the active site. Consequently, these constraints enable the zero-shot model to predict distal mutations more precisely. By integrating sequence, evolutionary, and dynamic information, our approach expands the diversity of candidate sites while maintaining a manageable screening scale, offering an efficient and generalizable strategy for enzyme engineering.<\/jats:p>","DOI":"10.1021\/acs.jctc.6c00829","type":"journal-article","created":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T07:02:03Z","timestamp":1786345323000},"page":"8607-8616","source":"Crossref","is-referenced-by-count":0,"title":["Prediction of Distal\nMutation Effects in Enzymes via\nIntegration of Molecular Dynamics Descriptors and Zero-Shot Model"],"prefix":"10.1021","volume":"22","author":[{"given":"Yiqiu","family":"Wang","sequence":"first","affiliation":[{"name":"Xiamen University , , ,","place":["Xiamen, P. R. China, 361005"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4825-0343","authenticated-orcid":true,"given":"Ding","family":"Luo","sequence":"additional","affiliation":[{"name":"Xiamen University , , ,","place":["Xiamen, P. R. China, 361005"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuming","family":"Cheng","sequence":"additional","affiliation":[{"name":"Xiamen University , , ,","place":["Xiamen, P. R. China, 361005"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3353-9411","authenticated-orcid":true,"given":"Binju","family":"Wang","sequence":"additional","affiliation":[{"name":"Xiamen University , , ,","place":["Xiamen, P. R. China, 361005"]},{"name":"Innovation Laboratory for Sciences and Technologies of Energy Materials of Fujian Province (IKKEM) , ,","place":["Xiamen, P. R. China, 361005"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,8,10]]},"reference":[{"issue":"4","key":"2026083118573308900_cit1","doi-asserted-by":"publisher","first-page":"279","DOI":"10.1038\/s43588-025-00788-8","article-title":"Physics-based modeling\nin the new era of enzyme engineering","volume":"5","author":"Jurich","year":"2025","journal-title":"Nat. Comput.\nSci."},{"issue":"9","key":"2026083118573308900_cit2","doi-asserted-by":"publisher","first-page":"1446","DOI":"10.1038\/s42256-025-01103-w","article-title":"Accelerating\nprotein engineering with fitness landscape modelling and reinforcement\nlearning","volume":"7","author":"Sun","year":"2025","journal-title":"Nat. Mach. 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Sci."},{"issue":"5","key":"2026083118573308900_cit6","doi-asserted-by":"publisher","first-page":"762","DOI":"10.1002\/pro.2648","article-title":"Prediction\nof distal residue participation in enzyme catalysis","volume":"24","author":"Brodkin","year":"2015","journal-title":"Protein Sci."},{"issue":"11","key":"2026083118573308900_cit7","doi-asserted-by":"publisher","first-page":"6503","DOI":"10.1021\/acs.chemrev.5b00590","article-title":"Protein Allostery and Conformational Dynamics","volume":"116","author":"Guo","year":"2016","journal-title":"Chem. Rev."},{"issue":"5","key":"2026083118573308900_cit8","doi-asserted-by":"publisher","first-page":"2499","DOI":"10.1021\/acs.jcim.1c00318","article-title":"D3DistalMutation: a\nDatabase to Explore the Effect\nof Distal Mutations on Enzyme Activity","volume":"61","author":"Wang","year":"2021","journal-title":"J. Chem.\nInf. Model."},{"key":"2026083118573308900_cit9","doi-asserted-by":"publisher","first-page":"108094","DOI":"10.1016\/j.biotechadv.2023.108094","article-title":"Role of distal sites in enzyme engineering","volume":"63","author":"Gu","year":"2023","journal-title":"Biotechnol. Adv."},{"issue":"34","key":"2026083118573308900_cit10","doi-asserted-by":"publisher","first-page":"30723","DOI":"10.1021\/jacs.5c05134","article-title":"Distal Mutations in a Designed Retro-Aldolase Alter\nLoop Dynamics to Shift and Accelerate the Rate-Limiting Step","volume":"147","author":"Hunt","year":"2025","journal-title":"J. Am. Chem. Soc."},{"issue":"1","key":"2026083118573308900_cit11","doi-asserted-by":"publisher","first-page":"8662","DOI":"10.1038\/s41467-025-63802-7","article-title":"Distal mutations\nenhance catalysis in designed enzymes\nby facilitating substrate binding and product release","volume":"16","author":"Zarifi","year":"2025","journal-title":"Nat. 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Food Chem."},{"issue":"21","key":"2026083118573308900_cit29","doi-asserted-by":"publisher","first-page":"13733","DOI":"10.1021\/acscatal.1c03950","article-title":"In Silico Identification and Experimental Validation of Distal Activity-Enhancing\nMutations in Tryptophan Synthase","volume":"11","author":"Maria-Solano","year":"2021","journal-title":"ACS Catal."},{"issue":"10","key":"2026083118573308900_cit30","doi-asserted-by":"publisher","first-page":"7112","DOI":"10.1109\/TPAMI.2021.3095381","article-title":"ProtTrans: Toward Understanding the Language\nof Life Through Self-Supervised Learning","volume":"44","author":"Elnaggar","year":"2022","journal-title":"IEEE\nTrans. Pattern Anal. Mach. Intell."},{"key":"2026083118573308900_cit31","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s41587-025-02836-0","article-title":"A trimodal protein language\nmodel enables advanced protein searches","author":"Su","year":"2025","journal-title":"Nat.\nBiotechnol."},{"issue":"1","key":"2026083118573308900_cit32","doi-asserted-by":"publisher","first-page":"321","DOI":"10.1021\/acssynbio.5c00755","article-title":"EvoZymePro-Cat: A Protein\u2013Ligand-Aware\nDeep Learning Framework\nfor Predicting Mutation Effects in Enzyme Function","volume":"15","author":"Xu","year":"2026","journal-title":"ACS Synth. Biol."},{"issue":"2","key":"2026083118573308900_cit33","doi-asserted-by":"publisher","first-page":"128","DOI":"10.1038\/nbt.3769","article-title":"Mutation\neffects\npredicted from sequence co-variation","volume":"35","author":"Hopf","year":"2017","journal-title":"Nat. Biotechnol."},{"key":"2026083118573308900_cit34","first-page":"8844","article-title":"MSA Transformer","volume-title":"Proceedings\nOf The 38th International Conference On Machine Learning","author":"Rao","year":"2021"},{"issue":"6637","key":"2026083118573308900_cit35","doi-asserted-by":"publisher","first-page":"1123","DOI":"10.1126\/science.ade2574","article-title":"Evolutionary-scale\nprediction of atomic-level protein structure with\na language model","volume":"379","author":"Lin","year":"2023","journal-title":"Science"},{"key":"2026083118573308900_cit36","article-title":"SaProt: Protein Language Modeling with Structure-aware\nVocabulary","volume-title":"The Twelfth International Conference\non Learning Representations","author":"Su","year":"2024"},{"key":"2026083118573308900_cit37","doi-asserted-by":"publisher","first-page":"35700","DOI":"10.52202\/079017-1126","article-title":"ProSST: Protein Language Modeling\nwith Quantized Structure and Disentangled Attention","volume-title":"Advances in Neural Information Processing Systems","author":"Li","year":"2024"},{"issue":"Supplement_1","key":"2026083118573308900_cit38","doi-asserted-by":"publisher","first-page":"i401","DOI":"10.1093\/bioinformatics\/btaf189","article-title":"From high-throughput\nevaluation to wet-lab studies: advancing mutation effect prediction\nwith a retrieval-enhanced model","volume":"41","author":"Tan","year":"2025","journal-title":"Bioinformatics"},{"key":"2026083118573308900_cit39","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s41587-025-02859-7","article-title":"Democratizing protein language model training,\nsharing and collaboration","author":"Su","year":"2025","journal-title":"Nat. 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