Molecular simulations explore disruptive actions of membrane-active peptides in lipid membranes

Abstract

Membrane-active peptides represent a wide class of short-sequenced proteins, which have a disruptive effect on the structural integrity of cell membranes. The underlying molecular processes by which membrane-active peptides disrupt cell membranes are poorly understood, and elucidation of the mechanisms is critical to deciphering the molecular basis for a number of diseases and developing novel therapeutics for these diseases. My PhD work has mainly investigated the actions of arginine-rich cell penetrating peptides (ARCPPs) and the cationic antimicrobial peptides (CAMPs) in the model cell membrane (lipid bilayer) environment. ARCPPs and CAMPs both have a high content of cationic amino acids, i.e., arginine and/or lysine and are able to readily adsorb onto and permeate cell membranes. This phenomenon poses a critical challenge to the widely-accepted view that cell membranes are natural protective barriers, which significantly inhibit the permeation of polar and charged solutes. Molecular dynamics (MD) simulations have been performed to shed new insights into the membrane permeation mechanisms of ARCPPs and CAMPs. The molecular simulation results unveil the importance of cooperative action by these peptides in kinetically stabilizing thermally nucleated membrane defects or pores. Pores nucleate spontaneously in lipid membranes due to membrane thermal fluctuations. Nevertheless, spontaneous pore formation is thermodynamically unfavourable and the hydrophobic character causes membrane pores to close quickly, via coordinated lipid movement. Using MD simulations, we have found that oligo-arginine (a cell-penetrating peptide) and melittin (an antimicrobial peptide) can kinetically stabilize thermal pores, causing significant slowing-down of their closure by hindering the cooperative motion of the lipids. This “hijacking” of thermal pores may allow multiple peptides to aggregate within them to form a kinetically stable peptide-pore complex. In marked contrast, the cationic oligo-lysine peptide does not possess this ability. In fact it seems to accelerate pore closure. The membrane defect mediated, cooperative actions of oligoarginine and melittin unveiled in this work could be a general mechanism whereby varieties of membrane-active peptides, including cell penetrating peptides, antimicrobial peptides and also amyloidal peptides are able to permeate or damage cell membranes via kinetically stabilized membrane pores.