Structure and dynamics of Penetratin’s association and translocation to a lipid bilayer

Penetratin belongs to the important class of small and positively charged peptides, capable of enteringcells. Thedetermination of the optimal peptidic structure for translocation is challenging; resultsobtained so far are varied and dependent on several factors. In this work, we review thedynamics of association of Penetratin with a modeled dioleoyl-phosphatidylcholine (DOPC)lipidmembraneusing molecular dynamics simulations with last generation force fields. Penetratin’sstructural preferences are determined using a Markov state model. It is observed that thepeptide retainsa helical form in the membrane associated state, just as in water, with the exception of bothtermini which lose helicity, facilitating the interaction of terminal residues with the phosphate groupson the membrane’s outer layer. The optimal orientation for insertion is found to be withthe peptide’s axis forming a small angle with the interface, and with R1 stretching towardthe bilayer. The interaction between arginine side-chains and phosphate groups is foundto be greater than the corresponding to lysine, mainly due to a higher number of hydrogenbonds between them. The freeenergy profile of translocation is qualitatively studied using UmbrellaSampling. It is found that there are different paths of penetration, that greatly differin size of freeenergy barrier. The lowest path is compatible with residues R10 to K13leading the way through the membrane and pulling the rest of the peptide. When the other side isreached, the C-terminus overtakes those residues, and finally breaks out of themembrane.The peptide’s secondarystructure during this traversal suffers some changes with respect to theassociation structure but, overall, conserves its helicity, with both termini in a moredisordered state