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They enable quantum-level accuracy for localized chemistry at substantially reduced cost. However, reliable coupling across region boundaries and application in heterogeneous environments remains a central challenge. Here, we extend the buffer region embedding strategy (BuRNN) for hybrid machine-learned interaction potentials\/molecular mechanics (MLIP\/MM) simulations in complex environments. The buffer region elevates the interactions of the inner region with its immediate surroundings to the MLIP level, whereas the interactions within the buffer region and with the outer region are still described at the MM level. We validate the approach across four test systems of increasing complexity: methanol\/water mixtures benchmarked against experimental total X-ray structure factors, a functionalized fullerene designed to describe a covalent boundary between the buffer and outer region, aqueous heme b with an axial cysteine ligand to probe coordinative bond dissociation, and the resting-state of the cytochrome P450 1A2 enzyme. Across these systems, BuRNN reproduces experimental observables or the underlying QM reference data and yields stable dynamics, including challenging metal\u2013ligand interactions. We compare explicit and implicit link-atom treatments at the buffer\u2013outer boundary and find that explicit capping provides more robust uncertainty estimates, which is critical for active-learning model generation. These results establish BuRNN as a practical approach to perform MLIP\/MM simulations in biomolecular systems.<\/jats:p>","DOI":"10.1021\/acs.jcim.6c00924","type":"journal-article","created":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T13:02:54Z","timestamp":1785934974000},"page":"10019-10032","source":"Crossref","is-referenced-by-count":0,"title":["Buffer Region Embedding\nfor Hybrid Machine-Learned\/Molecular-Mechanical\nSimulations in Complex Environments"],"prefix":"10.1021","volume":"66","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8081-6373","authenticated-orcid":true,"given":"Michael","family":"Caspary","sequence":"first","affiliation":[{"name":"BOKU University , , ,","place":["Vienna, Austria, 1190"]},{"name":"BOKU University , , ,","place":["Vienna, Austria, 1190"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9293-8562","authenticated-orcid":true,"given":"Radek","family":"Crha","sequence":"additional","affiliation":[{"name":"BOKU University , , ,","place":["Vienna, Austria, 1190"]},{"name":"BOKU University , , ,","place":["Vienna, Austria, 1190"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9821-6218","authenticated-orcid":true,"given":"Edgar","family":"Galicia-Andre\u0301s","sequence":"additional","affiliation":[{"name":"BOKU University , , ,","place":["Vienna, Austria, 1190"]},{"name":"BOKU University , , ,","place":["Vienna, Austria, 1190"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Poliak","sequence":"additional","affiliation":[{"name":"BOKU University , , ,","place":["Vienna, Austria, 1190"]},{"name":"Slovak University of Technology in Bratislava , , Radlinske\u0301ho 9 , ,","place":["Bratislava, Slovakia, 81237"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4232-2556","authenticated-orcid":true,"given":"Chris","family":"Oostenbrink","sequence":"additional","affiliation":[{"name":"BOKU University , , ,","place":["Vienna, Austria, 1190"]},{"name":"BOKU University , , ,","place":["Vienna, Austria, 1190"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,8,4]]},"reference":[{"key":"2026083104311724200_cit1","doi-asserted-by":"publisher","first-page":"10037","DOI":"10.1021\/acs.chemrev.0c00868","article-title":"Four Generations\nof High-Dimensional Neural Network Potentials","volume":"121","author":"Behler","year":"2021","journal-title":"Chem. 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