Drug design against antimicrobial resistance

Cell penetrating peptides are extensively studied due to their potential for having antimicrobial properties. The purpose of this study is to understand the mechanisms of certain cell penetrating peptides in bacterial and mammalian membranes and to research their potential in antimicrobial drug design. In this study, melittin and pVEC peptide structures along with POPC and POPE membranes were constructed in VMD and the passage of each peptide through bilayers of each membrane type were simulated using SMD simulations. MD simulations were carried out by taking snapshots of SMD simulations while the peptide was located on the top, middle, and bottom of the bilayer. The simulations were examined by following energy, force and work vs. distance profiles of peptides. The results gave insight on melittin and pVEC interactions with POPE and POPC membranes as they are transported through bilayers. Compared to POPE membrane, the electrostatic energies were higher in POPC membrane making it harder for peptides to penetrate the bilayer. Melittin helicity was higher in POPE bilayer. The observed lower helicity in POPC membrane is thought to facilitate pore formation by increasing interactions of residues with membrane lipids and effecting lipid orders. In POPE membrane another mechanism might be at work. POPE membrane thinned more which may increase the probability of leakage. The pVEC peptide lead to more water insertion inside the bilayers compared to melittin peptide. Furthermore, pVEC caused more water molecules to penetrate POPC membrane. This may increase the permeability of the membrane and increase uptake of more peptides. In MD simulations, pVEC preferred POPE membrane over POPC membrane while melittin had affinity for both membranes. When melittin center of mass was pulled, due to energy barriers melittin penetrated the upper P layer of the bilayer with difficulty but caused more water penetration into the bilayer compared to other simulations. When melittin was pulled with 1/10th velocity, it stayed in a parallel position on the upper P layer of membrane in α-helix structure before penetration. After 151.68 ns, melittin only reached the center of the bilayer while in other melittin POPE simulations it took melittin 58, 50 and 38 ns to pass through the bilayer.