Abstract
We performed coarse-grained simulations of the antimicrobial peptides Magainin-2, BP100, MSI-103, and MSI-78 on a phase-separated membrane to study their preference for the different domains. All the peptides displayed a clear preference for the liquid-disordered (Ld) phase over the liquid-ordered (Lo) one. For BP100, MSI-103, and MSI-78 there was a further preference of the peptides for the domain interface. The peptides’ preference toward the disordered phase was shown to reflect a penalization of lipid–lipid interaction enthalpy in the Lo phase, when in the vicinity of peptides. Similar results were observed at the two studied concentrations, although Ld phase saturation at the higher concentration drove some of the peptide excess to the Lo phase. Magainin-2 and MSI-103 were found to dimerize, in agreement with available experimental data. Interestingly, at high concentrations of Magainin-2 toroidal pores spontaneously formed in the Ld phase. We performed additional simulations to characterize this phenomenon, which is likely related to Magainin-2’s membranolytic action.
Highlights
Membrane lipid heterogeneity is crucial for various processes in living cells
Used model systems are bilayers composed of ternary mixtures of cholesterol, saturated, and unsaturated lipids, which yield a rich phase behavior at physiological temperatures (Feigenson, 2006)
Our findings show that antimicrobial peptides (AMPs) disrupt lipid– lipid interactions in both phases, but mostly in the Lo phase
Summary
Membrane lipid heterogeneity is crucial for various processes in living cells. Functions attributed to the membrane lipidome range from specific integral protein solvation (Contreras et al, 2011) to signaling (Forrester et al, 2004; Golub et al, 2004) to formation of spatial domains of different local composition (Simons and Toomre, 2000). Used model systems are bilayers composed of ternary mixtures of cholesterol, saturated, and unsaturated lipids, which yield a rich phase behavior at physiological temperatures (Feigenson, 2006). Over a range of component concentrations these ternary mixtures laterally separate into a liquid-ordered (Lo) phase, enriched in the saturated lipid and cholesterol, and a liquid-disordered (Ld) one, enriched in the unsaturated lipid (Veatch and Keller, 2003; Marsh, 2009; Dewitt and Dunn, 2015). While such lipid segregation has not been observed at large scales in cellular membranes, the phase-separated ternary mixture. Understanding the interplay between membrane proteins and such heterogeneous surroundings is central to shedding light on the function of both proteins and the associated lipids
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