ArticleJournal of chemical information and modeling2025
Quantum Mechanics/Molecular Mechanics Simulations Distinguish Insulin-Regulated Aminopeptidase Substrate (Oxytocin) and Inhibitor (Angiotensin IV) and Reveal Determinants of Activity and Inhibition.
Article in Journal of chemical information and modeling, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.
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1 citing paper in PubMed.
- All Roads Lead to Carbinolamine: QM/MM Study of Enzymatic C-N Bond Cleavage in Anaerobic Glycyl Radical Enzyme Choline Trimethylamine-Lyase (CutC).The journal of physical chemistry. B · 2025Article
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7 authors.
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Abstract
Insulin-regulated aminopeptidase (IRAP) is a zinc-dependent metalloenzyme identified as a novel target for combating diabetes-induced diseases due to its crucial role in glucose metabolism and insulin sensitivity regulation. IRAP's catalytic domain catalyzes the N-terminal peptide bond hydrolysis of natural substrate oxytocin, a neuroactive peptide linked to improved cognition and other elemental brain functions. Angiotensin IV and similar peptides are recognized as cognitive enhancers due to their ability to competitively inhibit IRAP's proteolytic activity, thereby mitigating natural neuropeptide degradation. Despite a very similar binding complex between the substrate and the inhibitor with IRAP, particularly around the scissile bond, it is unclear why the enzyme metabolizes oxytocin but does not efficiently degrade angiotensin IV. We employed enhanced sampling quantum mechanics/molecular mechanics (QM/MM) molecular dynamics simulations and higher-level QM/MM calculations to explore the reaction of these two peptides in IRAP. The calculated energy barrier for oxytocin cleavage was in very good agreement with the experimental data. A significantly higher energy barrier for the formation of the oxyanion tetrahedral intermediate (TI) and a higher overall barrier for the peptide cleavage were observed for the reaction with angiotensin IV. Comprehensive electronic structure analysis utilizing NBO and NCI methods unveiled the molecular basis for different reactivity, a stabilizing interaction between the sigma hole of the N-terminus disulfide bond and the hybridizing lone pair of the scissile peptide nitrogen in oxytocin. The interplay between a weak noncovalent spodium bond and strong bidentate coordination of the catalytic Zn
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