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 compared to synthetic monophospho and dephospho analogues with different biological activities in the Limulus assay. The conformation of glucosamine disaccharide headgroup, order and packing of fatty acid chains, solvation of phosphate groups, coordination by water molecules, sodium counterions and models of cationic amino acid side chains were described in terms of mean values, mean residence times, radial distribution functions, coordination numbers, solvation and interaction energies. Solvation and polar interactions of the phosphate groups were correlated to known biological activities the lipid A variants. The observed relationship between the biological effect and the number and position of the phosphate groups were explained with the help of simple mechanistic models of lipid A action. The possible mechanism of action involving specific binding of lipid A disaccharide headgroup to cationic residues of a receptor model was compared with an alternative mechanism, which assumes a relationship between the ability to adopt non-lamellar supramolecular structures and the biological activity. Conclusions are drawn about the probable mode of lipid A action. Implications for rational drug design of endotoxin-neutralising agents are discussed.