{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T22:58:11Z","timestamp":1790204291711,"version":"4.1.0"},"reference-count":70,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2022,9,6]],"date-time":"2022-09-06T00:00:00Z","timestamp":1662422400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["11932013"],"award-info":[{"award-number":["11932013"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["2021YFC2009201"],"award-info":[{"award-number":["2021YFC2009201"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["11932013"],"award-info":[{"award-number":["11932013"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2021YFC2009201"],"award-info":[{"award-number":["2021YFC2009201"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The pathogenesis of type 2 diabetes (T2D) is highly related to the abnormal self-assembly of the human islet amyloid polypeptide (hIAPP) into amyloid aggregates. To inhibit hIAPP aggregation is considered a promising therapeutic strategy for T2D treatment. Melatonin (Mel) was reported to effectively impede the accumulation of hIAPP aggregates and dissolve preformed fibrils. However, the underlying mechanism at the atomic level remains elusive. Here, we performed replica-exchange molecular dynamics (REMD) simulations to investigate the inhibitory effect of Mel on hIAPP oligomerization by using hIAPP20\u201329 octamer as templates. The conformational ensemble shows that Mel molecules can significantly prevent the \u03b2-sheet and backbone hydrogen bond formation of hIAPP20\u201329 octamer and remodel hIAPP oligomers and transform them into less compact conformations with more disordered contents. The interaction analysis shows that the binding behavior of Mel is dominated by hydrogen bonding with a peptide backbone and strengthened by aromatic stacking and CH\u2013\u03c0 interactions with peptide sidechains. The strong hIAPP\u2013Mel interaction disrupts the hIAPP20\u201329 association, which is supposed to inhibit amyloid aggregation and cytotoxicity. We also performed conventional MD simulations to investigate the influence and binding affinity of Mel on the preformed hIAPP1\u201337 fibrillar octamer. Mel was found to preferentially bind to the amyloidogenic region hIAPP20\u201329, whereas it has a slight influence on the structural stability of the preformed fibrils. Our findings illustrate a possible pathway by which Mel alleviates diabetes symptoms from the perspective of Mel inhibiting amyloid deposits. This work reveals the inhibitory mechanism of Mel against hIAPP20\u201329 oligomerization, which provides useful clues for the development of efficient anti-amyloid agents.<\/jats:p>","DOI":"10.3390\/ijms231810264","type":"journal-article","created":{"date-parts":[[2022,9,6]],"date-time":"2022-09-06T20:52:51Z","timestamp":1662497571000},"page":"10264","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Melatonin Inhibits hIAPP Oligomerization by Preventing \u03b2-Sheet and Hydrogen Bond Formation of the Amyloidogenic Region Revealed by Replica-Exchange Molecular Dynamics Simulation"],"prefix":"10.3390","volume":"23","author":[{"given":"Gang","family":"Wang","sequence":"first","affiliation":[{"name":"Key Laboratory of Exercise and Health Sciences (Ministry of Education), School of Kinesiology, Shanghai University of Sport, 399 Changhai Road, Shanghai 200438, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyi","family":"Zhu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Exercise and Health Sciences (Ministry of Education), School of Kinesiology, Shanghai University of Sport, 399 Changhai Road, Shanghai 200438, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaona","family":"Song","sequence":"additional","affiliation":[{"name":"Key Laboratory of Exercise and Health Sciences (Ministry of Education), School of Kinesiology, Shanghai University of Sport, 399 Changhai Road, Shanghai 200438, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingwen","family":"Zhang","sequence":"additional","affiliation":[{"name":"College of Physical Education and Training, Shanghai University of Sport, 399 Changhai Road, Shanghai 200438, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3921-3818","authenticated-orcid":false,"given":"Zhenyu","family":"Qian","sequence":"additional","affiliation":[{"name":"Key Laboratory of Exercise and Health Sciences (Ministry of Education), School of Kinesiology, Shanghai University of Sport, 399 Changhai Road, Shanghai 200438, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,9,6]]},"reference":[{"key":"ref_1","unstructured":"(2022, August 02). 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