Host Defense Peptides: Molecular Details of Attack on Bacterial and Neoplastic Mammalian Model Membranes

Abstract

Membrane-active host defense peptides constitute a key part of the initial immune response in multicellular organisms. They interact with anionic lipids of bacterial membranes and are also active against neoplastic mammalian membranes. The non-specific nature of these interactions reduces the propensity for developing resistance to antimicrobial and anticancer therapies but makes development of highly effective peptides a challenging task. Various mechanisms of peptide-membrane activity were proposed, but the molecular picture is still incomplete. We employ our novel highly mobile membrane mimetic (HMMM) model with enhanced lipid mobility, combined with all-atom molecular dynamics simulations to investigate structural and dynamic properties determining initial lipid-peptide interactions of magainin 2 (MAG2) and its highly charged variant, paxiganan (MSI-78). Extended multiple simulations were performed of MAG2 and MSI-78 monomers with HMMM binary membranes representing bacterial (PE/PG) and neoplastic (PC/PS) membranes. Spontaneous association of the peptides with the membranes lead to significant clustering of anionic lipids in both membrane models, lending support to the lipid clustering model as a potential first stage of the interaction. Interestingly, membrane surface rupture was observed as a result of lipid rearrangement. PE/PG membranes appear to be more susceptible than PC/PS to rupture by both peptides, which correlates well with recent experimental observations. PE/PG appears to offer easier entry for the charged residues due to hydrogen bonding and lack of positive charges on the PE head groups that may repel the cationic peptides. We propose a “sweep-and-anchor” mechanism that initiates membrane rupture: initial clustering of charged lipids by the charged residues is creating more loose domain boundaries in which hydrophobic residues can penetrate, creating a pore in membrane leaflet. Prior to the development of the HMMM method these inquiries were out of reach of atomistic simulations.