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These symptoms (along with particularly high serotonin levels) have been reported in patients with two missense variants in MAO-A (p.R45W and p.E446K). Herein, we report molecular simulations of the rate-limiting step of MAO-A-catalyzed serotonin degradation for these variants. We found that the R45W mutation causes a 6000-fold slowdown of enzymatic function, whereas the E446K mutation causes a 450-fold reduction of serotonin degradation rate, both of which are practically equivalent to a gene knockout. In addition, we thoroughly compared the influence of enzyme electrostatics on the catalytic function of both the wild type MAO-A and the p.R45W variant relative to the wild type enzyme, revealing that the mutation represents a significant electrostatic perturbation that contributes to the barrier increase. Understanding genetic disorders is closely linked to understanding the associated chemical mechanisms, and our research represents a novel attempt to bridge the gap between clinical genetics and the underlying chemical physics.<\/jats:p>","DOI":"10.1038\/s41598-022-26296-7","type":"journal-article","created":{"date-parts":[[2022,12,19]],"date-time":"2022-12-19T10:03:19Z","timestamp":1671444199000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Brunner syndrome caused by point mutation explained by multiscale simulation of enzyme reaction"],"prefix":"10.1038","volume":"12","author":[{"given":"Alja","family":"Prah","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Domen","family":"Pregeljc","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jernej","family":"Stare","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janez","family":"Mavri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,12,19]]},"reference":[{"key":"26296_CR1","doi-asserted-by":"crossref","first-page":"239821281879927","DOI":"10.1177\/2398212818799271","volume":"2","author":"NJ Bray","year":"2019","unstructured":"Bray, N. 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