Surface charge and fatty acids modulate the membrane permeation rate of cell-penetrating-peptides: Adsorption energy counterbalances pore formation cost

VIA M.A. (ORADOR); WILKE, NATALIA; DEL PÓPOLO, MARIO G.

Castellón de la Plana

Congreso; 6th International Iberian Biophysics Congress and X Iberoamerican Congress of Biophysics; 2018

Sociedad de Biofísica de España

Cell-penetrating-peptides (CPPs) are rich in basic aminoacids, which make peptides charged andhydrophilic at physiological pH. Following these traits, the observations that CPPs translocate lipidbilayers conferring cell-internalization ability to membrane impermeable cargos are counterintuitiveand deserve scrutiny at the molecular level. Membrane properties, such as lipid composition andsurface charge, regulate the rate and efficiency of the translocation process. In this work, we useMolecular Dynamics simulations and free-energy calculations to demonstrate that the presence offatty acids and other negatively charged lipids in the membrane boosts the translocation rate of atypical CPP. We focus on Arg9, and compare its translocation efficiency with that of a hydrophilicbut non-CPP peptide, Gly9. We also show that when the latter is chemically bound to Arg9, Arg9-Gly9 crosses the membrane with a lower free energy cost than Gly9 alone. We explain our findingsthrough a simple phenomenological model that considers the energy gained upon adsorption of thetranslocating molecule, and the energy barrier that must be surmounted to bring the molecule fromthe surface to the centre of the bilayer. Our simulations show that sufficiently strong binding to themembrane surface and negatively charged fatty acids enhance the so called CPP-effect.