Membrane active peptides with the ability to cross the plasma membrane represent a promising class of therapeutic compounds. However, translocation efficacy and membrane toxicity of these peptides appear correlated and a better understanding of their mechanisms of action is needed to achieve the desired effect. Here, a range of coarse grain molecular dynamics simulations have been performed to systematically investigate the interactions of such cell-penetrating peptides (CPPs) with biologically relevant membranes. Challenges associated to the development of a suitable asymmetric mammalian membrane model demonstrated the importance of lipid species distribution on the bilayer mechanical properties, as well as the effect of coarse graining on its electrostatic properties. However, simulations successfully discriminated between two CPPs, penetratin and transportan, and were consistent with the experimental data available for these. The results obtained suggest that the ability of transportan peptides to aggregate into flexible, dynamic, transmembrane bundles is responsible for their relative membrane toxicity. The stability and structure of these aggregates, as well as the extent of the bilayer perturbations they induced, were shown to depend on the membrane composition and asymmetry, thus providing a molecular basis to explain how the toxicity of CPPs is modulated by membranes. In particular, bilayer destabilisation was enhanced by the presence of anionic lipids and hampered by that of cholesterol. Transportan aggregates were also observed to trigger lipid flip-flops above a certain size and a new pathway for such events, not relying on the formation of water defects, was characterised.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:647570 |
| Date | January 2014 |
| Creators | Hélie, Jean |
| Contributors | Sansom, Mark S. P.; Deane, Charlotte M.; Milletti, Francesca |
| Publisher | University of Oxford |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://ora.ox.ac.uk/objects/uuid:1f154de5-6073-4bc6-986a-397734f5f140 |
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