Translocation of a single Arg9 peptide across a DOPC/ DOPG(4:1) model membrane using the weighted ensemble method

It is difficult to observe a spontaneous translocation of cell-penetrating peptides(CPPs) within a short time scale (e.g., a few hundred ns) in all-atom molecular dynamics(MD) simulations because the time required for the translocation of usual CPPs is on the order of minutes or so. In this work, we report a spontaneous translocation of a single Arg(9)(R9) across a DOPC/DOPG(4:1) model membrane within an order of a few tens ns scale by using the weighted ensemble(WE) method. We identify how water molecules and the orientation of Arg(9) play a role in translocation. We also show how lipid molecules are transported along with Arg(9). In addition, we present free energy profiles of the translocation across the membrane using umbrella sampling and show that a single Arg(9) translocation is energetically unfavorable. We expect that the WE method can help study interactions of CPPs with various model membranes within MD simulation approaches.

Automated summary

In this study, we used the weighted ensemble method to observe the spontaneous translocation of a single Arg(9) peptide across a DOPC/DOPG(4:1) model membrane within a few tens of nanoseconds. We found that water molecules and the orientation of Arg(9) played important roles in the translocation process and showed how lipid molecules were transported with Arg(9). Additionally, we presented the free energy profiles of translocation and demonstrated that translocation of a single Arg(9) was energetically unfavorable. We expect that the weighted ensemble method can facilitate the study of interactions between cell-penetrating peptides and various model membranes in molecular dynamics simulations.