Conformational simulation of phosphosphingolipids by molecular mechanics

Force field parameters were developed for the phosphodiester linkage and in troduced into the molecular mechanics program MM3 to simulate conformationa l states of phosphosphingolipids. The modified MM3 parameter set was tested with the dimethylphosphate anion and the methylphosphorylcholine zwitterio n. The results compare well with established conformational preferences of these important functionalities in lipid head groups. At a dielectric const ant of epsilon = 4.0, generally taken to represent the electrostatic enviro nment of the membrane surface, the diesterphosphate dihedral angles alpha(2 ) and alpha(3) are predicted to be primarily + sc, + sc in both species. Th e outer dihedral angles alpha(4) and alpha(5) of the choline functionality are predominantly ap and +/- sc, respectively, in the lowest energy structu res. Increase of the dielectric constant reveals an extension of these part ially folded structures as might occur under the influence of an aqueous en vironment. This parameter set was then applied to a phosphorylated dihydroc eramide to investigate conformational preferences of the head group with re spect to the lipid interface. Three of the most probable conformations are compatible with liquid crystalline, bilayer organizations. These conformati ons exhibit intramolecular hydrogen bonds involving the NH and OH moieties as donors and an ester and/or anionic phosphate oxygen as accepters. Featur es of the Boltzmann-distributed conformations are confirmed by known experi mental results from NMR spectroscopy. (C) 1999 Elsevier Science B.V. All ri ghts reserved.