Unravelling the Cell-Penetrating Potential of Endogenous Opioid Neuropeptide Dynorphin A through Computational Dissection of Membrane Disruption Principles

Dynorphins are endogenous neuropeptides that function as opioids. In addition to opioid activity, dynorphins can induce several pathological effects such as neurological dysfunctions and cell death. Previous studies have suggested that Dynorphin A (DynA) and its clinical variants (L5S, R6W, and R9C) mediate some pathogenic actions through formation of transient pores in lipid domains of the plasma membrane. Here, we use a combination of steered and conventional molecular dynamics simulations to evaluate the ability of DynA and its variants to disturb lipid membranes in comparison to well established cell-penetrating peptides to determine how these peptides interact and permeate model lipid bilayers. We show that in our setup DynA and its variants (except for R9C) exhibit a strong membrane disturbing potential that may lead to translocation through the formation of water pores, which is likely prevented in cholesterol containing bilayers for R6W. When cholesterol and negative charge in the bilayers are present, the membrane disruption potential of DynA and its variants is minimal, but the hydrophobic-to-polar substitution in L5S favors peptide translocation. Altogether, these results show the importance of out-of-the-box computational studies to design membrane disruptive peptides to exploit their cell-penetrating and antimicrobial capabilities.