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Using all\u2010atom molecular dynamics simulations (200\u2009ns\u2009\u00d7\u20093 independent replicates per system), we examined the interactions of a pre\u2010assembled Alyteserin\u20101c hexamer with simplified bilayer models representing Gram\u2010positive (75% PG\/25% PE) and Gram\u2010negative (75% PE\/25% PG) bacterial inner membranes. The hexameric assembly maintained structural stability and substantial \u03b1\u2010helical content throughout all simulations, with oligomeric cohesion associated primarily with hydrophobic packing of residues L10, L13, V14, I17, and F6. Cationic residues K7 and K15 remained lipid\u2010exposed with near\u2010permanent headgroup contact occupancy, suggesting their role as principal membrane\u2010anchoring sites. Comparative membrane analyses indicated greater lateral lipid mobility, lower bilayer density, and stronger local acyl chain perturbation in the Gram\u2010negative membrane model, consistent with greater membrane susceptibility at lower peptide concentrations. Helix orientation and pore geometry analyses were inconsistent with stable barrel\u2010stave transmembrane pore formation and instead supported interfacial or transient toroidal\u2010like membrane perturbations. Transient single\u2010file water threading was observed in the Gram\u2010positive system, while perturbations in the Gram\u2010negative membrane remained predominantly surface\u2010localized. These findings provide a computationally derived mechanistic framework for the membrane selectivity of Alyteserin\u20101c and may inform rational design of membrane\u2010targeting antimicrobial peptides. Given the simplified bilayer models, pre\u2010assembled oligomeric assumption, and accessible simulation timescales, the proposed mechanisms should be interpreted as hypothesis\u2010generating rather than definitive.<\/jats:p>","DOI":"10.1002\/mbo3.70327","type":"journal-article","created":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T03:57:36Z","timestamp":1781150256000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Exploring the Mechanism of Alyteserin\u20101c in Gram\u2010Positive and Gram\u2010Negative Bacterial Membrane Models Using a Computational Approach"],"prefix":"10.1002","volume":"15","author":[{"given":"Akshay","family":"Sasidharan","sequence":"first","affiliation":[{"name":"Quantitative Biology Lab, Department of Integrative Biology, School of Bio Sciences and Technology Vellore Institute of Technology (VIT Deemed to be University) Vellore Tamil Nadu India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rajasekaran","family":"Ramalingam","sequence":"additional","affiliation":[{"name":"Quantitative Biology Lab, Department of Integrative Biology, School of Bio Sciences and Technology Vellore Institute of Technology (VIT Deemed to be University) Vellore Tamil Nadu India"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,6,10]]},"reference":[{"key":"e_1_2_14_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.softx.2015.06.001"},{"key":"e_1_2_14_3_1","doi-asserted-by":"publisher","DOI":"10.3390\/biom9100527"},{"key":"e_1_2_14_4_1","doi-asserted-by":"publisher","DOI":"10.3390\/ph6121543"},{"key":"e_1_2_14_5_1","doi-asserted-by":"crossref","unstructured":"Bechinger B. \u201cStructure and Functions of Channel\u2010Forming Peptides: Magainins Cecropins Melittin and Alamethicin.\u201d1997.","DOI":"10.1007\/s002329900201"},{"key":"e_1_2_14_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/0006-2952(90)90138-B"},{"key":"e_1_2_14_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrmicro1098"},{"key":"e_1_2_14_8_1","doi-asserted-by":"publisher","DOI":"10.3390\/antibiotics13111076"},{"key":"e_1_2_14_9_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00232-021-00174-1"},{"key":"e_1_2_14_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.peptides.2009.03.004"},{"key":"e_1_2_14_11_1","doi-asserted-by":"publisher","DOI":"10.1063\/1.464397"},{"key":"e_1_2_14_12_1","doi-asserted-by":"publisher","DOI":"10.3390\/membranes15060161"},{"key":"e_1_2_14_13_1","doi-asserted-by":"publisher","DOI":"10.1039\/D1RA06267K"},{"key":"e_1_2_14_14_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.1003033"},{"key":"e_1_2_14_15_1","article-title":"Lipid17: A Comprehensive AMBER Force Field for the Simulation of Zwitterionic and Anionic Lipids","author":"Gould I.","year":"2018","journal-title":"Manuscript Preparation"},{"key":"e_1_2_14_16_1","unstructured":"Gowers R. 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