Data from: Elucidating the impact of red blood cell membrane components on melittin-induced pore formation with molecular dynamics simulations

Understanding the membrane-disrupting mode of action of antimicrobial
peptides (AMPs) in complex biological membranes is critical for the design
of therapeutically viable AMPs that are both active against microbial
pathogens and nontoxic to human cells. To assess human toxicity in AMP
design studies, melittin (MEL) – a highly charged 26-amino acid AMP
sourced from bee venom – is often used as the positive control in
experimental human red blood cell (RBC) hemolysis assays. Molecular
dynamics (MD) simulations have proved invaluable in elucidating the
pore-formation mechanism of MEL in single-lipid zwitterionic membranes.
However, modeling pore formation in lipid bilayers containing multiple
lipid species, like RBC membranes, has been limited due to the challenges
of using atomistic MD simulations to capture long-timescale membrane
restructuring events that depend on lipid heterogeneity, leaflet
asymmetry, and cholesterol content. To address these challenges and access
larger time scales, in this work, we utilize the coarse-grained MARTINI
force field to model four lipid membranes of increasing complexity,
ranging from single-lipid POPC membranes to asymmetric RBC-mimetic
membranes containing cholesterol. Through the application of a nucleation
collective variable (ξ) to create transmembrane pores and a
coarse-grained-to-atomistic backmapping strategy, we studied MEL
pore-lining affinity and pore nucleation free energies to assess the
effect of lipid complexity and cholesterol on MEL pore formation. We find
that although cholesterol strongly inhibits MEL-induced pore formation
regardless of lipid content, pore nucleation is more favorable in RBC
versus single-lipid POPC membranes when cholesterol is absent due to the
enrichment of anionic POPS lipids near the pore that permits increased
conformational flexibility for MEL. These results provide new physical
insight into factors that affect pore formation in compositionally complex
membranes and are a step toward understanding how AMPs can be designed to
selectively induce pores in membranes with different compositions.