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In this study, we introduce a coupled simulation workflow that combines classical molecular dynamics (MD) with high-throughput quantum mechanical (QM) analysis to reveal the electronic structure signatures of mutation-induced drug resistance in the HIV-1 protease. Our workflow leverages GPU-accelerated MD to generate conformational ensembles, and performs in operando linear-scaling density functional theory (DFT) calculations on selected frames parallelized on a coupled partition of CPU nodes. This design enables efficient, massively parallel quantum analysis of protein\u2013ligand complexes at atomic resolution. Using this approach, we investigate resistance to the antiviral Darunavir in a multimutant HIV-1 protease variant. By mapping the network of electronic interactions across the binding interface, our results highlight the critical role of conformational sampling and quantum insight in understanding distal mutation effects, and demonstrate a scalable computational strategy for studying complex biophysical mechanisms of drug resistance. We argue that this type of analysis may pave the way for designing inhibitors that maintain binding stability against systemic, mutation-induced destabilization.<\/jats:p>","DOI":"10.1021\/acs.jctc.6c01377","type":"journal-article","created":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T16:02:31Z","timestamp":1789747351000},"page":"10165-10179","source":"Crossref","is-referenced-by-count":0,"title":["Coupling Quantum\nMechanical Modeling and Molecular\nDynamics on Heterogeneous Supercomputers for Studying Distal Mutation\nEffects on Drug Binding in HIV-1"],"prefix":"10.1021","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4480-8565","authenticated-orcid":true,"given":"William","family":"Dawson","sequence":"first","affiliation":[{"name":"RIKEN Center for Computational Science , , ,","place":["Kobe, Hyogo, Japan, 650-0047"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Louis","family":"Beal","sequence":"additional","affiliation":[{"name":"Inria Centre at the University Grenoble Alpes, Inovalle\u0301e , 655 Avenue de l\u2019Europe, CS 90051 , ,","place":["Montbonnot, France, Cedex 38334"]},{"name":"Inria Centre at Rennes University, Campus Universitaire de Beaulieu , Avenue du General Leclerc , ,","place":["Rennes, France, Cedex 35042"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Zaccaria","sequence":"additional","affiliation":[{"name":"University Grenoble Alpes, MEM, L_Sim , ,","place":["Grenoble, France, F-38000"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1747-0247","authenticated-orcid":true,"given":"Luigi","family":"Genovese","sequence":"additional","affiliation":[{"name":"University Grenoble Alpes, MEM, L_Sim , ,","place":["Grenoble, France, F-38000"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,9,18]]},"reference":[{"key":"2026101310071007500_cit1","doi-asserted-by":"crossref","DOI":"10.1002\/9783527671816","volume-title":"Atomistic\nComputer Simulations: A Practical Guide","author":"Bra\u0301zdova\u0301","year":"2013"},{"key":"2026101310071007500_cit2","doi-asserted-by":"publisher","DOI":"10.1002\/wcms.1574","article-title":"Density functional theory calculations\nof large systems:\nInterplay between fragments, observables, and computational complexity","volume":"12","author":"Dawson","year":"2022","journal-title":"WIREs Comput. 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