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However, the mechanism of peptide accumulation and associated cytotoxicity remains unclear. Due to the unique properties and significant role of histidine in protein sequences, here for the first time, the tautomeric effect of histidine at the early stages of amylin misfolding was investigated via molecular dynamics simulations. Considering Tau and Pi tautomeric forms of histidine (Tau and Pi tautomers are denoted as \u03f5 and \u03b4, respectively), simulations were performed on two possible isomers of amylin. Our analysis revealed a higher probability of transient \u03b1\u2010helix generation in the \u03b4 isomer in monomeric form. In dimeric forms, the \u03b4\u03b4 and \u03b4\u03f5 conformations showed an elevated amount of \u03b1\u2010helix and lower coil in comparison to the \u03f5\u03f5 dimer. Due to the significant role of \u03b1\u2010helix in membrane disruption and transition to \u03b2\u2010sheet structure, these results may imply a noticeable contribution of the \u03b4 isomer and the \u03b4\u03b4 and \u03b4\u03f5 dimers rather than \u03f5 and \u03f5\u03f5 conformations in the early stages of diabetes initiation. Our results may aid in elucidating the hIAPP self\u2010association process in the etiology of amyloidosis.<\/jats:p>","DOI":"10.1002\/asia.202100641","type":"journal-article","created":{"date-parts":[[2021,7,6]],"date-time":"2021-07-06T23:10:02Z","timestamp":1625613002000},"page":"2453-2462","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Histidine Tautomerism Driving Human Islet Amyloid Polypeptide Aggregation in the Early Stages of Diabetes Mellitus Progression: Insight at the Atomistic Level"],"prefix":"10.1002","volume":"16","author":[{"given":"Abbas","family":"Salimi","sequence":"first","affiliation":[{"name":"Department of Chemistry Sungkyunkwan University  Suwon 16419 South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sompriya","family":"Chatterjee","sequence":"additional","affiliation":[{"name":"Department of Chemistry Sungkyunkwan University  Suwon 16419 South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin","family":"Yong Lee","sequence":"additional","affiliation":[{"name":"Department of Chemistry Sungkyunkwan University  Suwon 16419 South Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,7,19]]},"reference":[{"key":"e_1_2_7_1_1","unstructured":"\u00a0"},{"key":"e_1_2_7_2_2","doi-asserted-by":"publisher","DOI":"10.1039\/c3cp90062b"},{"key":"e_1_2_7_3_2","doi-asserted-by":"publisher","DOI":"10.1002\/prot.24338"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2012.02.031"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.diabres.2009.10.007"},{"key":"e_1_2_7_6_1","unstructured":"\u00a0"},{"key":"e_1_2_7_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.diabres.2018.02.023"},{"key":"e_1_2_7_8_2","unstructured":"World Health Organization G. 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