Nisin/lipid II interaction in bacterial membrane: molecular dynamics study
The worldwide rapid emergence of resistant bacteria put at threat the efficacy of antibiotics, thus the development of novel antibacterial agents is urgently needed. The cell wall precursor lipid II consisting the chemically conservative pyrophosphate group represents a promising pharmaceutical target. Antimicrobial peptides, that target lipid II, i.e. lantibiotic nisin, could be excellent prototypes for new generation antibiotics due to their low liability to develop resistance. Understanding of molecular mechanism of initial stages of membrane-bound lipid II recognition by water-soluble nisin is indispensable, in order to improve the peptide structure and properties into pharmaceutically applicable
form. Here, we present a molecular dynamics simulation study of initial stages of the aforementioned recognition. In membrane environment, lipid II adopts very few conformations characterized by unique spatial arrangement of hydrogen bond acceptors in the pyrophosphate group at the bilayer surface. These acceptors are efficiently captured by NH groups of nisin, thus explaining its high selectivity to lipid II. Similarly, rings A and B of nisin, which are known to recognize lipid II, adopt the only stable conformation in the presence of dimethylpyrophosphate, which mimics the binding determinant of lipid II. Finally, we propose molecular model of nisin (rings A and B) / lipid II complex in bacterial membrane, which may be employed for design of novel antibiotic prototypes.