Polymyxin B nonapeptide: Conformations in water and in the lipopolysaccharide-bound state determined by two-dimensional NMR and molecular dynamics

Polymyxin B nonapeptide (PMN) is a derivative of polymyxin B, an α,γ-diaminobutyric acidrich decapeptide from Bacillus polymyxa that displays antimicrobial and lipopolysaccharide (LPS)-antagonistic activities. The conformations of PMN in aqueous solution as well as in the LPS-bound state have been studied by ¹H two-dimensional nmr methods in conjunction with molecular dynamics techniques. The aqueous structure of the free peptide is characterized by a type II' β-turn centered around D-Phe⁵ and Leu⁶, and an inverse γ-turn at Thr⁹. The LPS-bound conformation of PMN was studied by transferred nuclear Overhauser effect experiments. The essential features of the cyclic portion of free aqueous PMN are mostly preserved when the peptide is bound to LPS; however, the linear dipeptide fragment as well as the side chains of the heptatpeptide ring show a conformational change and a reduction in mobility. The LPS-bound PMN structure was used to construct a model of the lipid A-polymyxin B (decapeptide) complex, which allows the rationalization of several experimental observations concerning the binding of polymyxin to, and consequent neutralization of, the toxicity of LPS, and may be of value in the rational therapeutic targeting of endotoxin.