{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,24]],"date-time":"2025-11-24T16:12:43Z","timestamp":1764000763226,"version":"build-2065373602"},"reference-count":46,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2021,6,23]],"date-time":"2021-06-23T00:00:00Z","timestamp":1624406400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia","doi-asserted-by":"publisher","award":["IF\/00052\/2014, 2020.01423.CEECIND and UID\/Multi\/04378\/2020"],"award-info":[{"award-number":["IF\/00052\/2014, 2020.01423.CEECIND and UID\/Multi\/04378\/2020"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Processes"],"abstract":"<jats:p>Statins are important drugs in the regulation of cholesterol levels in the human body that have as a primary target the enzyme \u03b2-hydroxy-\u03b2-methylglutaryl-CoA reductase (HMGR). This enzyme plays a crucial role in the mevalonate pathway, catalyzing the four-electron reduction of HMG-CoA to mevalonate. A second reduction step of this reaction mechanism has been the subject of much speculation in the literature, with different conflicting theories persisting to the present day. In this study, the different mechanistic hypotheses were evaluated with atomic-level detail through a combination of molecular dynamics simulations (MD) and quantum mechanics\/molecular mechanics (QM\/MM) calculations. The obtained Gibbs free activation and Gibbs free reaction energy (15 kcal mol\u22121 and \u221240 kcal mol\u22121) show that this hydride step takes place with the involvement of a cationic His405 and Lys639, and a neutral Glu98, while Asp715 remains in an anionic state. The results provide an atomic-level portrait of this step, clearly demonstrating the nature and protonation state of the amino acid residues involved, the energetics associated, and the structure and charge of the key participating atoms in the several intermediate states, finally elucidating this missing step.<\/jats:p>","DOI":"10.3390\/pr9071085","type":"journal-article","created":{"date-parts":[[2021,6,23]],"date-time":"2021-06-23T03:22:00Z","timestamp":1624418520000},"page":"1085","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["A QM\/MM Evaluation of the Missing Step in the Reduction Mechanism of HMG-CoA by Human HMG-CoA Reductase"],"prefix":"10.3390","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1280-2524","authenticated-orcid":false,"given":"Paula","family":"Mihaljevi\u0107-Juri\u010d","sequence":"first","affiliation":[{"name":"Structural Biology of the Cell Laboratory UMR 7654 CNRS, \u00c9cole Polytechnique, 91128 Palaiseau, France"},{"name":"Department of Chemistry, University of Osijek, Ulica cara Hadrijana 8\/A, 31000 Osijek, Croatia"},{"name":"UCIBIO\/REQUIMTE, BioSIM\u2014Department of Biochemistry, Faculty of Medicine, University of Porto, Alameda Professor Hernani Monteiro, 4200-319 Porto, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6560-5284","authenticated-orcid":false,"given":"S\u00e9rgio F.","family":"Sousa","sequence":"additional","affiliation":[{"name":"UCIBIO\/REQUIMTE, BioSIM\u2014Department of Biochemistry, Faculty of Medicine, University of Porto, Alameda Professor Hernani Monteiro, 4200-319 Porto, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2021,6,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"5715","DOI":"10.1021\/acs.biochem.8b00869","article-title":"New Crystallographic Snapshots of Large Domain Movements in Bacterial 3-Hydroxy-3-methylglutaryl Coenzyme A Reductase","volume":"57","author":"Ragwan","year":"2018","journal-title":"Biochemistry"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"19933","DOI":"10.1074\/jbc.M213006200","article-title":"Crystal structure of a statin bound to a class II hydroxymethylglutaryl-CoA reductase","volume":"278","author":"Tabernero","year":"2003","journal-title":"J. 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