Mathath, A.V.Chakraborty, D.2026-02-032024Journal of Chemical Physics, 2024, 161, 16, pp. -219606https://doi.org/10.1063/5.0226869https://idr.nitk.ac.in/handle/123456789/20868Using a well-developed reaction coordinate in umbrella sampling, we studied the single peptide permeation through a model cancerous cell membrane, varying the hydrophilicity and the charge of the peptides. Two peptides, melittin and pHD108, were studied. The permeation mechanism differs from a barrel-stave-like mechanism to toroidal pore and vesicle formation based on the number and the placement of the hydrophilic amino acids in the peptide. Membrane curvature changes dynamically as the permeation process occurs. In the case of vesicles, the peptide traverses along a smooth, homogenous pathway, whereas a rugged, steep pathway was found when lipid molecules did not line up along the wall of the membrane (barrel-stave-like mechanism). A mechanism similar to a toroidal pore consists of multiple minima. Higher free energy was found for the permeating terminal containing charged amino acid residues. Vesicle formation was found for pHD108 peptide N-terminal with a maximum membrane thinning effect of 54.4% with free energy cost of 8.20 ± 0.10 kcal mol?1 and pore radius of 2.33 ± 0.07 nm. Insights gained from this study can help to build synthetic peptides for drug delivery. © 2024 Author(s).Amino acidsCell membranesControlled drug deliveryNafion membranesPeptidesTargeted drug deliveryAmino-acidsCancerous cellsHydrophilicsMelittinMembrane curvatureMembrane permeationPore formationReaction coordinatesUmbrella samplingVesicles formationPermeationmelittinpeptidecell membranecell membrane permeabilitychemical phenomenachemistrylipid bilayermetabolismmolecular dynamicsCell MembraneCell Membrane PermeabilityHydrophobic and Hydrophilic InteractionsLipid BilayersMelittenMolecular Dynamics Simulation