Interactions of Two Amphipathic Cell-Penetrating Peptides with Complex Model Membranes: Insights from Molecular Dynamics Simulations

Abstract

Cell-penetrating peptides (CPP) can permeate cellular membranes and are therefore attractive vectors for gene therapy and drug delivery. However their uptake mechanisms are still poorly understood [1]. Peptides classified as CPP are usually enriched in basic residues and thus positively charged but except from this shared characteristic display a wide range of physico-chemical properties. A unifying interpretation of experimental results is rendered all the more difficult by the great diversity in experimental setups; nevertheless there is evidence that some CPP can be internalized by both endocytic and direct translocation pathways. In particular, peptide concentration and amphipathicity have been shown to be important for membrane disruption and passive permeation. Membrane lipid composition and electrostatic properties also appear to play a crucial role in the peptides activity.Here we apply multi-scale molecular dynamics simulations to gain molecular level insights into the interactions of both a primary amphipathic CPP (Transportan) and a secondary amphipathic CPP (Penetratin) with model membranes. Coarse-grained (CG) simulations were performed to investigate the behaviour of the peptides over several microseconds in large, asymmetric bilayers with complex, biologically relevant lipid compositions. The influence of peptide secondary structure was also explored. The CG simulations highlighted different lipid bilayer perturbations by the two peptides. Membrane permeation was investigated further using more detailed simulation methods (both CG simulations with polarisable water model and atomistic representations).[1] A. Ziegler, Thermodynamic studies and binding mechanisms of cell-penetrating peptides with lipids and glycosaminoglycans, Adv. Drug Del. Rev. 60 (2008) 580-597.