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However, the physio-chemical mechanisms of how these hIAPP aggregates trigger membrane damage are unclear. Using coarse-grained and all-atom molecular dynamics simulations, we investigated the role of lipid nanodomains in the presence or absence of anionic lipids, phosphatidylserine (PS), and a ganglioside (GM1), in the membrane disruption and protein folding behaviors of hIAPP aggregates on phase-separated raft membranes. Our raft membranes contain liquid-ordered (Lo), liquid-disordered (Ld), mixed Lo\/Ld (Lod), PS-cluster, and GM1-cluster nanosized domains. We observed that hIAPP aggregates bound to the Lod domain in the absence of anionic lipids, but also to the GM1-cluster- and PS-cluster-containing domains, with stronger affinity in the presence of anionic lipids. We discovered that L16 and I26 are the lipid anchoring residues of hIAPP binding to the Lod and PS-cluster domains. Finally, significant lipid acyl chain order disruption in the annular lipid shells surrounding the membrane-bound hIAPP aggregates and protein folding, particularly beta-sheet formation, in larger protein aggregates were evident. We propose that the interactions of hIAPP and both non-anionic and anionic lipid nanodomains represent key molecular events of membrane damage associated with the pathogenesis of amyloid diseases.<\/jats:p>","DOI":"10.3390\/molecules28104191","type":"journal-article","created":{"date-parts":[[2023,5,19]],"date-time":"2023-05-19T10:08:55Z","timestamp":1684490935000},"page":"4191","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Exploring the Role of Anionic Lipid Nanodomains in the Membrane Disruption and Protein Folding of Human Islet Amyloid Polypeptide Oligomers on Lipid Membrane Surfaces Using Multiscale Molecular Dynamics Simulations"],"prefix":"10.3390","volume":"28","author":[{"given":"Ngoc","family":"Nguyen","sequence":"first","affiliation":[{"name":"Physics Department, Trinity University, San Antonio, TX 78212, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amber","family":"Lewis","sequence":"additional","affiliation":[{"name":"Neuroscience Department, Trinity University, San Antonio, TX 78212, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thuong","family":"Pham","sequence":"additional","affiliation":[{"name":"Physics Department, Trinity University, San Antonio, TX 78212, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1109-6872","authenticated-orcid":false,"given":"Donald","family":"Sikazwe","sequence":"additional","affiliation":[{"name":"Pharmaceutical Sciences Department, Feik School of Pharmacy, University of the Incarnate Word, San Antonio, TX 78209, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kwan H.","family":"Cheng","sequence":"additional","affiliation":[{"name":"Physics Department, Trinity University, San Antonio, TX 78212, USA"},{"name":"Neuroscience Department, Trinity University, San Antonio, TX 78212, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,5,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"137","DOI":"10.3390\/biophysica1020011","article-title":"Amyloid-Mediated Mechanisms of Membrane Disruption","volume":"1","author":"Sciacca","year":"2021","journal-title":"Biophysica"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"454","DOI":"10.1021\/ar200189b","article-title":"Membrane disruption and early events in the aggregation of the diabetes related peptide IAPP from a molecular perspective","volume":"45","author":"Brender","year":"2012","journal-title":"Acc. 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