Molecular Dynamics Simulation Studies of Antimicrobial Cyclo-RRRWFW and Its Analogs in Water and POPC Bilayers

Antimicrobial peptides (AMPs) are part of the innate immune system of many organisms. They mostly target bacterial membrane via carpet model and ⁄ or formation of pores. Thus, there is a reduced likelihood for bacteria to show resistance towards them. Membrane permeabilization by AMPs depends mainly on both electrostatic accumulation near negatively charged bacterial membrane and hydrophobic insertion into membranes which finally results in a breakdown of barrier function of lipid matrix. To study lipid bilayers-AMPs interactions at atomic levels, molecular dynamic (MD) simulation studies have extensively been used. cyclo-RRRWFW (c-WFW) is an AMP from a group of small hexapeptides which shows good/excellent activity against E. coli. c-WFW interacts strongly with neutral and negatively charged lipid bilayers; however, less information is available on its binding to lipid bilayers in atomistic details. Here, we investigated MD simulations of c-WFW and its analogs, i.e., cyclo-RRRWWF, cyclo-RRNalNalRF, cyclo-RRWWRF, cyclo-KKWWKF, and cyclo-RRYYRF in water and POPC bilayer. Simulations were carried out in GROMACS using CHARMM36 force field with lipid, peptides, and TIP3P water model standard parameters in the presence of NaCl. POPC bilayer consisting of around 238 lipids were used and equilibrated for at least 50 ns until the area per lipid converges close to ˜ 63 − 65 A per headgroup. The peptides are put close to POPC ( ≤ 10 A) to reduce the cost of simulations. All simulations were done under P = 1 atm.; T = 310 K. The RMSD and Rgyr values reflecting overall stability of the peptides were computed.