Molecular dynamics study on lipid A from Escherichia coli: insights into its mechanism of biological action

Structural properties of the Escherichia coli lipid A moiety were analysed by means of molecular mechanics and molecular dynamics simulations and comp ared to synthetic monophospho and dephospho analogues with different biolog ical activities in the Limulus assay. The conformation of glucosamine disac charide headgroup, order and packing of fatty acid chains, solvation of pho sphate groups, coordination by water molecules, sodium counterions and mode ls of cationic amino acid side chains were described in terms of mean value s, mean residence times, radial distribution functions, coordination number s, solvation and interaction energies. Solvation and polar interactions of the phosphate groups were correlated to known biological activities the lip id A variants. The observed relationship between the biological effect and the number and position of the phosphate groups were explained with the hel p of simple mechanistic models of lipid A action. The possible mechanism of action involving specific binding of lipid A disaccharide headgroup to cat ionic residues of a receptor model was compared with an alternative mechani sm, which assumes a relationship between the ability to adopt non-lamellar supramolecular structures and the biological activity. Conclusions are draw n about the probable mode of lipid A action. Implications for rational drug design of endotoxin-neutralising agents are discussed. (C) 2000 Elsevier S cience B.V. All rights reserved.