Characterization of Anticancer Peptides in Membrane Disruption

Abstract

Cationic antimicrobial peptides have long been shown to disrupt membranes or display anticancer activity. A series of 18-20 residue anticancer peptides, with increasing hydrophobicities, have been designed to take advantage of the electronegativity of tumor cells, which arises from the aberrant lipid composition of the outer leaflet of the cell membrane 1. The designed anticancer peptides preferentially fold to a β-hairpin at the surface of cancer cells, and contain alternating valine (V) and lysine (K) residues, representing the N- and C- terminal strand regions, with a defined turn region, made of four amino acids (-VPPT-). We have studied the process of membrane disruption by the above mentioned anticancer peptides, using coarse grained MARTINI model and atomistic molecular dynamics simulations. We have also studied the mechanism of action of these peptides under various lipid compositions of phosphatidylserine and phosphatidylcholine. Our results suggest that the primary driving force for membrane disruption is the electrostatic interaction between the anionic phosphatidyserine and the cationic anticancer peptides.1.Anticancer β-Hairpin Peptides: Membrane-Induced Folding Triggers Activity; Chomdao Sinthuvanich, Ana Salome Veiga, Kshitij Gupta, Diana Gaspar, Robert Blumenthal, and Joel P. Schneider; Journal of the American Chemical Society 2012 134 (14), 6210-6217