In silico study of nisin/lipid II molecular recognition
Given the challenge of global antibiotic resistance, the development of new medications is indispensable. Lipid II - bacterial cell wall precursor – is a promising pharmaceutical target for innovative antibiotics, whereas lantibiotic nisin, effectively capturing lipid II’s conservative pyrophosphate group, is a potential prototype of a new generation of antibiotics. Because the structure of membrane-bound lipid II/nisin complex is lacking, we studied their recognition via molecular dynamics (MD) simulations. As a result, the medium-driven dynamics of both partners in their parent environments was explored. The N-terminal 11-residue fragment of nisin, which recognizes lipid II in bacterial membrane, adopts a unique closed-ring conformation only in water solution - this was proven by recent NMR study. In this state, the peptide NH groups of the ring A orient toward a common center, forming a pool of H-bond donors. Based on MD data, it was shown that nisin in this conformation forms the most stable complex with pyrophosphate analogues mimicking the binding determinant of lipid II. Here, we describe the results of the detailed in silico study of nisin1-11 structure and dynamics in different solvents. Efficient conformational sampling and clustering of the MD states based on backbone coordinates and dihedral angles was performed. The results obtained were found to be environment-dependent. These findings may be further employed to improve the peptide structure in order to design its new pharmaceutically applicable forms.