Free Energy Calculations of the Transferring of a Cyclic Arginine 9 Peptide across a Lipid Bilayer Suggest a Water-Pore Assisted Mechanism

Abstract

Molecular details of translocation arginine rich cell penetrating peptides through lipid bilayers are still under debate. Any mechanism has to answer the central question that how a highly hydrophilic peptide is able to cross the hydrophobic core of lipid membrane. A possible mechanism involves the formation of a local water defect in the membrane such that the hydrophilic residues of the peptide are solvated throughout the translocating process. In this work, we calculate the free energy of forming a water pore, the translocation of the peptide with the pore formed, and translocation of the peptide without a water pore. Free energies are calculated along order parameters using umbrella sampling. The calculations shows that free energy of transferring the peptide into the bilayer through a path involving a water defect is lower than the path without a water defect. The free energy of forming a pore is around 100 KJ/mol. We will discuss the unsuitability of different pathways to describe the kinetics of peptide translocation. We expect these results could extend to arginine rich peptides, such as antimicrobial and cell-penetrating peptides, in general.