title: Cause and effect of melittin-induced pore formation: a computational approach.
abstract: Melittin embedded in a palmitoyl oleyl phosphatidylcholine bilayer at a high peptide/lipid ratio (1:30) was simulated in the presence of explicit water and ions. The simulation results indicate the incipience of an ion-permeable water pore through collective membrane perturbation by bound peptides. The positively charged residues of melittin not only act as "anchors" but also disrupt the membrane, leading to cell lysis. A detailed analysis of the lipid tail order parameter profile depicts localized membrane perturbation. The lipids in the vicinity of the aqueous cavity adopt a tilted conformation, which allows local bilayer thinning. The prepore thus formed can be considered as the melittin-induced structural defects in the bilayer membrane. Because of the strong cationic nature, the melittin-induced prepore exhibits selectivity toward anions over cations. As Cl(-) ions entered into the prepore, they are electrostatically entrapped by positively charged residues located at its wall. The confined motion of the Cl(-) ions in the membrane interior is obvious from calculated diffusion coefficients. Moreover, reorientation of the local lipids occurs in such a way that few lipid heads along with peptide helices can line the surface of the penetrating aqueous phase. The flipping of lipids argued in favor of melittin-induced toroidal pore over a barrel-stave mechanism. Thus, our result provides atomistic level details of the mechanism of membrane disruption by antimicrobial peptide melittin.
authors.affiliation: Department of Chemistry, University of Calcutta, 92, A. P. C. Road, Kolkata-700 009, India.
authors.forename: Moutusi
authors.initials: M
authors.lastname: Manna
authors.forename: Chaitali
authors.initials: C
authors.lastname: Mukhopadhyay
mesh_terms: D000595:Amino Acid Sequence; D002462:Cell Membrane / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D002463:Cell Membrane Permeability / Q000187:drug effects; D002712:Chlorides / Q000378:metabolism; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D057927:Hydrophobic and Hydrophilic Interactions; D007473:Ion Channels / Q000378:metabolism; D008051:Lipid Bilayers / Q000737:chemistry / Q000378:metabolism; D008555:Melitten / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D009068:Movement; D010713:Phosphatidylcholines / Q000737:chemistry / Q000378:metabolism; D016062:Porosity / Q000187:drug effects; D055503:Protein Multimerization; D055550:Protein Stability; D020836:Protein Structure, Quaternary; D012997:Solvents / Q000378:metabolism; D013379:Substrate Specificity; D014867:Water / Q000378:metabolism
chemical_list: D002712:Chlorides; D007473:Ion Channels; D008051:Lipid Bilayers; D010713:Phosphatidylcholines; D012997:Solvents; D014867:Water; D008555:Melitten; C028694:1-palmitoyl-2-oleoylphosphatidylcholine