Conformational simulation of phosphosphingolipids by molecular mechanics

Force field parameters were developed for the phosphodiester linkage and introduced into the molecular mechanics program MM3 to simulate conformational states of phosphosphingolipids. The modified MM3 parameter set was tested with the dimethylphosphate anion and the methylphosphorylcholine zwitterion. The results compare well with established conformational preferences of these important functionalities in lipid head groups. At a dielectric constant of epsilon = 4.0, generally taken to represent the electrostatic environment of the membrane surface, the diesterphosphate dihedral angles alpha(2) and alpha(3) are predicted to be primarily + sc, + sc in both species. The outer dihedral angles alpha(4) and alpha(5) of the choline functionality are predominantly ap and +/- sc, respectively, in the lowest energy structures. Increase of the dielectric constant reveals an extension of these partially folded structures as might occur under the influence of an aqueous environment. This parameter set was then applied to a phosphorylated dihydroceramide to investigate conformational preferences of the head group with respect to the lipid interface. Three of the most probable conformations are compatible with liquid crystalline, bilayer organizations. These conformations exhibit intramolecular hydrogen bonds involving the NH and OH moieties as donors and an ester and/or anionic phosphate oxygen as accepters. Features of the Boltzmann-distributed conformations are confirmed by known experimental results from NMR spectroscopy. (C) 1999 Elsevier Science B.V. All rights reserved.