When peptides tease membranes: a molecular dynamics investigation of cationic peptides on lipid bilayers

PUCHOL JOAQUIN; M. VIA; GALASSI, VANESA V.; N. WILKE,; DEL PÓPOLO, M. G.

Congreso; L Reunión Anual SAB; 2022

Cationic polypeptides (CPs) are part of a large family of peptides that are capable of permeating cell membranes. Their positive electric charge and secondary structure may contribute to their membrane-permeation activity, although many details of the permeation mechanism remain unclear. Cell penetrating peptides (CPPs) and antimicrobial peptides (AMPs) share the capability to disrupt cell membranes. The first ones are rich in arginine and lysine sequences, of up to 20 amino acids, and are involved in endogenous transport mechanisms and cellular transduction. On the other hand, AMPs are longer chains of up to 50 residues, also rich in hydrophobic amino-acids, that participate in the immune response of plants and animals. Their action mechanism involves the absorption to the target membrane, and some of them acquire an alpha-helix structure upon insertion, reminiscent of a corkscrew.CPs mildly perturb the structure of the bilayer as part of their adsorption and subsequent insertion mechanism. In addition, the surface net charge and the type of lipids that compose the membrane modulate the peptide-membrane binding strength. In this work we apply Molecular Dynamics simulations to characterize, structurally and energetically, the peptides-membranes interactions. Our models consist of bilayer patches with different lipid composition in contact with cationic polypeptides. We use the MARTINI coarse grained force field with nonaarginine (R9) and Polybia-MP1 as models of each type of peptide. As a first step, we focus on characterizing the interaction energy of Polybia-MP1, evidencing its capability to interact with anionic as well as zwitterionic membranes. Subsequently, the influence of the CPs on the membrane fluidity is assessed for membranes covered with R9. Capillary-waves analysis method, mean squared displacement and membrane curvature perturbation simulations are performed. Our results, along with previous results for R9, show that both cationic peptides preferably bind to anionic membranes, while Polybia-MP1 also binds to neutral membranes. Also, R9 yields a fluidification of the membrane that may affect the translocation mechanism.