Abstract
Infections of many virulent bacterial strains are triggered by the release of pore forming toxins (PFTs), whose primary function is the formation of oligomeric transmembrane pore complexes on the target plasma membrane. Lipids which are the major constituents of the plasma membrane undergo structural and dynamic reorganizations during the process of pore formation. Using all-atom molecular dynamics simulations, we investigate the changes in the structure and dynamics of lipids in a 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) lipid bilayer in the presence of contrasting PFTs, namely cytolysin-A (ClyA) an α toxin which forms a dodecameric pore and α-hemolysin (AHL) a β toxin which forms a heptameric pore. ClyA with its inserted wedge shaped bundle of inserted α helices induces significant asymmetry across the membrane leaflets as revealed in correlation functions, structure factors, tilt and deuterium order parameters. In contrast the protein modulated leaflet heterogeneities and hydrophobic mismatch are significantly smaller in the case of AHL. Both pore complexes induce significant dynamic heterogeneities as revealed in sub-diffusive mean squared displacements and multistep relaxation in the continuous survival probabilities of lipids. In general the spatial extent of dynamic heterogeneity due to the presence of the transmembrane pores was longer ranged than the shorter ranged structural heterogeneity. Displacement probability distributions show long tails and the distinctly non-Gaussian features reflect the induced dynamic heterogeneity. A detailed profiling of the protein-lipid contacts with residues tyrosine, tryptophan, lysine and arginine show increased non-polar contacts in the cytoplasmic leaflet for both PFTs, with a higher number of atomic contacts in the case of AHL in the extracellular leaflet due to the mushroom-like topology of the pore complex. An understanding of lipid rearrangement and membrane perturbation has broader implications in signal transduction and perturbations to the mechanical properties of the plasma membrane.
Footnotes
† Electronic Supplementary Information (ESI) available: [details of any supplementary information available should be included here]. See DOI: 00.0000/00000000.