Baxova, K. L.; Koikkara, J.; Allolio, C.

The enhanced cell penetration ability of arginine-rich peptides, such as nonaarginine (R9), compared to their lysine-rich counterparts remains incompletely understood. Atomistic simulations reveal that R9 binds significantly more strongly ({approx} 20 kJ/mol) and penetrates deeper into anionic lipid headgroup region than its lysine equivalent. This enhanced interaction translates into a stronger induction of negative membrane curvature by R9. We combine these data to construct a model of peptide binding and curvature induction in fusogenic lipid mixtures and employ a multiscale simulation approach, combining atomistic molecular dynamics (MD) with mesoscopic Monte Carlo (MC) simulations, to dissect the molecular basis and morphological consequences of arginine specificity. The results show that stable membrane invaginations, as observed in studies of cell penetration, require excess membrane and are stable only for R9 (outside of the domain of stability of the Helfrich stomatocyte). By analyzing lipid and protein sorting coupled to the membrane structure, we explain the interplay of Gaussian and mean curvature in providing a mechanistic basis for the initial membrane deformation events potentially involved in \'Arginine Magic\' cell entry pathways.