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Ideally, molecular dynamics simulations should sample all enzyme configurations along the reaction path using post\u2010Hartree\u2010Fock or DFT QM\/MM electrostatic embedding methods, but these are computationally expensive. Here, we introduce a simple approach to improve the third\u2010order density functional tight binding (DFTB3) semi\u2010empirical method to model hydride transfer reactions in enzymes. We identified deficiencies in DFTB3's description of the potential energy surface for the hydride transfer step in Crotonyl\u2010CoA Carboxylase\/Reductase (Ccr) and developed a systematic methodology to address these limitations. Our approach involves modifying DFTB3's repulsive potential functions using linear combinations of harmonic functions, guided by analysis of C\u2010H and C\u2010C distance distributions along the reaction path. The optimized DFTB3 Hamiltonian significantly improved the description of the hydride transfer reaction in Ccr, reproducing the reference DFT activation barrier within 0.1 kcal\/mol. We also addressed the transferability of our method by applying it to another hydride transfer reaction bearing the 1,4\u2010dihydropyridine motif but exhibiting distinct structural features of the reactant, as well as the hydride transfer reaction in Dihydrofolate Reductase (DHFR). In both cases, our adapted DFTB3 Hamiltonian correctly reproduced the DFT reference and experimentally observed activation barriers. The low computational cost and transferability of our method will enable more accurate and efficient QM\/MM molecular dynamics simulations of hydride transfer reactions, potentially accelerating research in enzyme engineering and drug design.<\/jats:p>","DOI":"10.1002\/jcc.70174","type":"journal-article","created":{"date-parts":[[2025,7,15]],"date-time":"2025-07-15T03:34:40Z","timestamp":1752550480000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Adapted DFTB3 Repulsive Potentials Reach DFT Accuracy for Hydride Transfer Reactions in Enzymes"],"prefix":"10.1002","volume":"46","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4941-6619","authenticated-orcid":false,"given":"Jos\u00e9 Lu\u00eds","family":"Vel\u00e1zquez\u2010Libera","sequence":"first","affiliation":[{"name":"Departamento de Qu\u00edmica F\u00edsica Universitat de Valencia  Valencia Spain"},{"name":"Departamento de Bioinform\u00e1tica, Centro de Bioinform\u00e1tica, Simulaci\u00f3n y Modelado (CBSM), Facultad de Ingenier\u00eda Universidad de Talca  Talca Chile"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rodrigo","family":"Recabarren","sequence":"additional","affiliation":[{"name":"Departamento de F\u00edsico\u2010Qu\u00edmica, Facultad de Ciencias Qu\u00edmicas Universidad de Concepci\u00f3n  Concepci\u00f3n Chile"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5555-8720","authenticated-orcid":false,"given":"David Adrian","family":"Saez","sequence":"additional","affiliation":[{"name":"Departamento de Ciencias B\u00e1sicas, Facultad de Ciencias Universidad del B\u00edo\u2010B\u00edo  Chill\u00e1n Chile"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carlos","family":"Castillo","sequence":"additional","affiliation":[{"name":"Departamento de F\u00edsico\u2010Qu\u00edmica, Facultad de Ciencias Qu\u00edmicas Universidad de Concepci\u00f3n  Concepci\u00f3n Chile"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4640-0419","authenticated-orcid":false,"given":"J. 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