Molecular Dynamics Insight into the Lipid II Recognition for the Lantibiotic Antimicrobial Agent Candidates : Cesin, Rombocin, and Nisin

Abstract

Antimicrobial agent is a substance that inhibits or kills microorganisms, but it may also contribute to antimicrobial resistance problem after prolonged exposure through structural mutation in the microorganism. Lipid II is a structure in the microorganism that is evolutionarily conserved despite the structural mutation and therefore very attractive as a drug target. Nisin is an antimicrobial agent from the lantibiotic group that target Lipid II using Ring A-B, coupled with its ability to create pores on the membrane using Ring D-E. Recent research found that cesin without the Ring D-E and rombocin without Ring E still exhibit similar inhibitory concentration compared to nisin, although the molecular information underlying this activity remains unclear. Here, we investigate how the ring A-B regions of cesin, rombocin, and nisin interact with dimethyl pyrophosphate (DMPPi), a molecule that mimics the pyrophosphate group of Lipid II. This study employed global molecular docking using AutoDock Vina to predict the binding pose, then, compared with the molecular dynamics simulation results using NAMD and further optimized with the local molecular docking around the lowest binding energy interaction position between the peptides and DMPPi. Interaction between DMPPi to cesin and rombocin indicate a better results compared to nisin.