{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T18:22:52Z","timestamp":1785435772707,"version":"3.56.0"},"reference-count":36,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T00:00:00Z","timestamp":1775001600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Science Foundation","award":["2107567"],"award-info":[{"award-number":["2107567"]}]},{"award":["2107567"],"award-info":[{"award-number":["2107567"]}],"id":[{"id":"https:\/\/ror.org\/021nxhr62","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Cyclotides are exceptionally stable plant peptides whose biological activity is widely attributed to interactions with lipid membranes, yet the molecular mechanisms underlying these interactions remain incompletely resolved. Here, we employ microsecond-scale (1 \u03bcs) all-atom molecular dynamics simulations to investigate the membrane association of the cyclotide kalata B1 with phospholipid bilayers of distinct headgroup composition, including POPC, POPE, and POPG. This extended timescale enables full bilayer equilibration and allows observation of slower peptide-induced membrane responses that are not accessible in shorter simulations. Across all systems, kalata B1 rapidly adsorbs to the membrane surface and remains predominantly surface-associated throughout the simulations, while the cyclic cystine knot motif remains structurally intact, confirming the exceptional robustness of the cyclotide fold during membrane engagement. Lipid-dependent differences arise primarily from variations in peptide orientation, conformational flexibility, and interfacial dynamics rather than deep bilayer insertion or pore formation. Zwitterionic POPC membranes favor compact, upright peptide configurations, whereas POPE and POPG bilayers promote enhanced lateral spreading and dynamic reorganization driven by hydrogen bonding and electrostatic interactions, respectively. Leaflet-resolved analyses of lipid contacts, membrane thickness, and area per lipid reveal localized, asymmetric perturbations confined to the peptide-exposed leaflet, with no evidence of sustained bilayer thinning or global destabilization. Together, these results support an interfacial, headgroup-dependent mechanism of cyclotide membrane activity and reconcile previous experimental observations. This work provides molecular-level insight into lipid selectivity and early-stage cyclotide\u2013membrane interactions that may inform future design of cyclotide-based bioactive agents.<\/jats:p>","DOI":"10.3390\/molecules31071168","type":"journal-article","created":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T10:09:21Z","timestamp":1775038161000},"page":"1168","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Molecular Dynamics Simulations Cyclotide Kalata B1 Interactions with Lipid Bilayers"],"prefix":"10.3390","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4083-8804","authenticated-orcid":false,"given":"Neville Y.","family":"Forlemu","sequence":"first","affiliation":[{"name":"School of Science and Technology, Chemistry Program, Georgia Gwinnett College, 1000 University Center Lane, Lawrenceville, GA 30043, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2159-3418","authenticated-orcid":false,"given":"Eric N.","family":"Njabon","sequence":"additional","affiliation":[{"name":"Department of Inorganic Chemistry, Faculty of Science, University of Yaound\u00e9 I, Yaound\u00e9 P.O. Box 812, Centre Region, Cameroon"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0090-0274","authenticated-orcid":false,"given":"Ajay","family":"Mallia","sequence":"additional","affiliation":[{"name":"School of Science and Technology, Chemistry Program, Georgia Gwinnett College, 1000 University Center Lane, Lawrenceville, GA 30043, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon","family":"Mwongela","sequence":"additional","affiliation":[{"name":"School of Science and Technology, Chemistry Program, Georgia Gwinnett College, 1000 University Center Lane, Lawrenceville, GA 30043, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sairam","family":"Tangirala","sequence":"additional","affiliation":[{"name":"School of Science and Technology, Chemistry Program, Georgia Gwinnett College, 1000 University Center Lane, Lawrenceville, GA 30043, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"4801","DOI":"10.1093\/jxb\/erw210","article-title":"Discovery, Structure, Function, and Applications of Cyclotides: Circular Proteins from Plants","volume":"67","author":"Weidmann","year":"2016","journal-title":"J. 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