Study of the Mecanism of Action of a Hybrid Peptide in POPG:POPC Bilayers

Abstract

A hybrid peptide sequence has been synthesized from the antimicrobial peptides pediocin A and plantaricin 149A. Previous studies of circular dichroism and fluorescence spectroscopic studies have shown a disordered to ordered conformational transition of the peptide upon binding to POPG but not to POPC. Further, single vesicle experiments under optical microscopy observation have indicated that at low concentrations the peptide causes the disruption of POPG membrane and formation of small, heterogeneous complexes of phospholipids and peptides. In order to analyze those interactions, concentration effects and to propose a disruption mechanism, molecular dynamics simulations were carried out using the GROMOS parameter set 54A7 and MARTINI. The systems were analyzed with respect to time-dependent (peptide secondary structure and lipid tilt angle), and average properties (density profiles and deuterium order parameters).It was found that the peptides adsorb on both PG and PC membranes via electrostatic interactions. Only upon binding to the PG surface there is an increase of helical content compared to the peptide in solution. Higher helical content is also observed for the single peptide embedded in PG compared to PC membranes. The density of the membrane medium makes conformational transition of the peptide embedded slower than on the surface of the membrane. Our simulations indicate disruption of the membrane without deep penetration of the peptides. Evidence for that comes from increased disorder of the membrane and persistent interactions between the peptide and membrane headgroups throughout the membrane disruption process. Our findings suggest that the hybrid peptide disrupt the membrane via a carpet-like mechanism which has also been postulated for the action of Pediocin A and Plantaricin 149A [1,2].[1] Gaussier et al. App. Environm. MicroBiol, 69, 6777 (2003);[2] Lopes et al., BBA, 1788, 2252 (2009).