Mechanism of the cell-penetrating peptide transportan 10 permeation of lipid bilayers.
The mechanism of the interaction between the cell-penetrating peptide transportan 10 (tp10) and phospholipid membranes was investigated. Tp10 induces graded release of the contents of phospholipid vesicles. The kinetics of peptide association with vesicles and peptide-induced dye efflux from the vesicle lumen were examined experimentally by stopped-flow fluorescence. The experimental kinetics were analyzed by directly fitting to the data the numerical solution of mathematical kinetic models. A very good global fit was obtained using a model in which tp10 binds to the membrane surface and perturbs it because of the mass imbalance thus created across the bilayer. The perturbed bilayer state allows peptide monomers to insert transiently into its hydrophobic core and cross the membrane, until the peptide mass imbalance is dissipated. In that transient state tp10 "catalyzes" dye efflux from the vesicle lumen. These conclusions are consistent with recent reports that used molecular dynamics simulations to study the interactions between peptide antimicrobials and phospholipid bilayers. A thermodynamic analysis of tp10 binding and insertion in the bilayer using water-membrane transfer hydrophobicity scales is entirely consistent with the model proposed. A small bilayer perturbation is both necessary and sufficient to achieve very good agreement with the model, indicating that the role of the lipids must be included to understand the mechanism of cell-penetrating and antimicrobial peptides.
Yandek
Lindsay E
LE
Department of Chemistry and Biochemistry, University of North Carolina Wilmington, Wilmington, North Carolina 28403, USA.
Pokorny
Antje
A
Florén
Anders
A
Knoelke
Kristina
K
Langel
Ulo
U
Almeida
Paulo F F
PF
D003198:Computer Simulation; D004058:Diffusion; D019004:Galanin / Q000737:chemistry*; D008051:Lipid Bilayers / Q000737:chemistry*; D008081:Liposomes / Q000737:chemistry*; D008560:Membrane Fluidity; D008956:Models, Chemical; D008958:Models, Molecular; D010539:Permeability; D010743:Phospholipids / Q000737:chemistry*; D016062:Porosity; D021381:Protein Transport; D011993:Recombinant Fusion Proteins / Q000737:chemistry*; D014862:Wasp Venoms / Q000737:chemistry*
D008051:Lipid Bilayers; D008081:Liposomes; D010743:Phospholipids; D011993:Recombinant Fusion Proteins; D014862:Wasp Venoms; C110068:transportan; D019004:Galanin