Detalle de: Membrane disruption potential of endogenous opioid neuropeptide Dynorphin A and related clinical variants

Dynorphins are natural neuropeptides that act like opioids but can also cause harmful effects like neurological issues and cell death. Dynorphin A (DynA WT) and its variants (L5S, R6W, and R9C) may disrupt lipid bilayers, leading to pathophysiological effects. Using steered and conventional molecular dynamics simulations, we evaluated how DynA and its variants interact with and penetrate model lipid bilayers. We defined three lipid compositions: neutral, cholesterol-rich and negatively charged, representing different sections of a cell membrane to characterize specific lipid-protein interactions. The R6W peptide cannot find a stable state in any membrane, always returning to the water-bilayer interface. DynA L5S uniquely disturbs neutral lipid bilayers by forming proteolipid pores at the hydrophobic core. DynA WT and L5S are capable to form more stable proteolipid pores in neutral bilayers with cholesterol. L5S and R9C disrupt negatively charged bilayers with cholesterol, again, being able to form stable toroidal pores. The computational strategy presented here allows to study how single amino acid changes in DynA peptides affect their ability to disturb different bilayer compositions.