PT  - JOURNAL ARTICLE
AU  - Thomas Tarenzi
AU  - Gianluca Lattanzi
AU  - Raffaello Potestio
TI  - Membrane binding of pore-forming γ-hemolysin components studied at different lipid compositions
AID  - 10.1101/2022.02.08.479512
DP  - 2022 Jan 01
TA  - bioRxiv
PG  - 2022.02.08.479512
4099  - http://biorxiv.org/content/early/2022/02/09/2022.02.08.479512.short
4100  - http://biorxiv.org/content/early/2022/02/09/2022.02.08.479512.full
AB  - Methicillin-resistant Staphylococcus aureus is is among those pathogens currently posing the highest threat to public health. Its host immune evasion strategy is mediated by pore-forming toxins (PFTs), among which the bicomponent γ-hemolysin is one of the most common. The complexity of the porogenesis mechanism by γ-hemolysin poses difficulties in the development of antivirulence therapies targeting PFTs from S. aureus, and sparse and apparently contrasting experimental data have been produced. Here, through a large set of molecular dynamics simulations at different levels of resolution, we investigate the first step of pore formation, and in particular the effect of membrane composition on the ability of γ-hemolysin components, LukF and Hlg2, to steadily adhere to the lipid bilayer in the absence of proteinaceous receptors. Our simulations are in agreement with experimental data of γ-hemolysin pore formation on model membranes, which are here explained on the basis of the bilayer properties. Our computational investigation suggests a possible rationale to explain experimental data on phospholipid binding to the LukF component, and to hypothesise a mechanism by which, on purely lipidic bilayers, the stable anchoring of LukF to the cell surface facilitates Hlg2 binding, through the exposure of its N-terminal region. We expect that further insights on the mechanism of transition between soluble and membrane bound-forms and on the role played by the lipid molecules will contribute to the design of antivirulence agents with enhanced efficacy against methicillin-resistant S. aureus infections.HighlightsThe presence of cholesterol and unsaturated phospholipid tails facilitates the binding of γ-hemolysin components, LukF and Hlg2, on model membranes.Coarse-grained simulations show that the two components have different absorption capabilities, with LukF undergoing the most stable binding.The spontaneous docking of LukF on the membrane is mediated by two distant phosphatidylcholine binding sites.Competing Interest StatementThe authors have declared no competing interest.