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However, it is not clear what advantage the tethering has, and therefore a computational study was performed. In particular, we report here the first computational study on the nonheme iron dioxygenase involved in the epoxidation reaction during the dapdiamide biosynthesis (DdaC) and investigate tethered and nontethered substrates. Molecular dynamics (MD) simulations show that the protein carrier applies pressure onto the surface of the protein and influences the fold and active site description and leads to differences in substrate\u2010oxidant interactions. Quantum chemical calculations give much lower epoxidation barriers for the activation of the tethered substrate by 7\u00a0kcal mol<jats:sup>\u22121<\/jats:sup> over the nontethered substrate and highlight the advantage of a tethered substrate in catalysis.<\/jats:p>","DOI":"10.1002\/chem.202501610","type":"journal-article","created":{"date-parts":[[2025,8,21]],"date-time":"2025-08-21T10:46:26Z","timestamp":1755773186000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Substrate Epoxidation Catalyzed by the Nonheme Iron Dioxygenase Dapdiamide Biosynthesis Enzyme C. 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