Coarse-grained simulations of hemolytic peptide δ-lysin interacting with a POPC bilayer

Abstract

δ-lysin, secreted by a Gram-positive bacterium Staphylococcus aureus, is a 26-residue membrane active peptide that shares many common features with antimicrobial peptides (AMPs). However, it possesses a few unique features that differentiate itself from typical AMPs. In particular, δ-lysin has zero net charge, even though it has many charged residues, and it preferentially lyses eukaryotic cells over bacterial cells. Here, we present the results of coarse-grained molecular dynamics simulations of δ-lysin interacting with a zwitterionic membrane over a wide range of peptide concentrations. When the peptides concentration is low, spontaneous dimerization of peptides is observed on the membrane surface, but deep insertion of peptides or pore formation was not observed. However, the calculated free energy of peptide insertion suggests that a small fraction of peptides is likely to be present inside the membrane at the peptide concentrations typically seen in dye efflux experiments. When the simulations with multiple peptides are carried out with a single pre-inserted transmembrane peptide, spontaneous pore formation occurs with a peptide-to-lipid ratio (P/L) as low as P/L = 1:42. Inter-peptide salt bridges among the transmembrane peptides seem to play a role in creating compact pores with very low level of hydration. More importantly, the transmembrane peptides making up the pore are constantly pushed to the opposite side of the membrane when the mass imbalance between the two sides of membrane is significant. Thus, the pore is very dynamic, allowing multiple peptides to translocate across the membrane simultaneously.

Differential Interaction of Antimicrobial Peptides with Lipid Structures Studied by Coarse-Grained Molecular Dynamics Simulations

“…These restrictions can be solved by the use of simplified coarse-grained (CG) models that nowadays have reached good agreement with atomically detailed simulations. Particularly, the MARTINI CG model has been used in several studies for the simulations of AMPs interacting with lipid bilayers, and has shown the formation of pores in some cases [ 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 ].…”

Effect of biphosphate salt on dipalmitoylphosphatidylcholine bilayer deformation by Tat polypeptide

“…One needs to address both the role of polypeptide sequence and salt in the medium. There are coarse-grained studies on polymer-membrane systems [17][18][19][20][21][22] where the structures of lipids, water, and amino acids are approximated by mapping several atoms into an equivalent particle in order to enable to study much larger systems and longer simulations. Martini coarse-grained force field provide important information on localization and translocation of CPPs across membranes.…”