| Molecular modeling studies were performed on functional fragments of sphingolipids (SLs) to validate conformational preferences inferred from IR and NMR spectroscopic analysis of their interfaces and head groups. Dimethylphosphate anion and its complex with water were used to model the phosphodiester linkage of the head group in sphingomyelin (SM), the most abundant SL in most mammalian cell membranes. Monomers and dimers of 2-aminoethanol served to study H-bonding tendencies in the interfacial region of SLs. Complexes of ethylene and allyl alcohol with one or two water molecules were modeled to confirm the plausibility of a O-Hπ (πH) bond involving the trans double bond between carbons 4 and 5 of the sphingoid base. High-level ab initio MP2 and hybrid density functional B3LYP calculations were used. The conformational preferences of sphingoid bases, sphingosine and sphinganine, were modeled using both empirical force field (MMFF94, OPLS-AA) and B3LYP calculations in combination with GB/SA and PCM implicit solvation models. The favored arrangements of the hydrophilic regions of both bases were not substantially different, in agreement with experimental observations. However, discrepancies were found in the results of the various modeling approaches. This indicates the need of additional parameterization of the force fields as well as the use of explicit hydration to obtain a better agreement between the experimental and calculated conformer distributions. The nature of H-bonding interactions and stereoelectronic preferences in molecular fragments of SLs and their clusters with water molecules were analyzed using Natural Bond Orbital and Atoms in Molecules theories.; The current results support the formation of extensive, cooperative and dynamic intra- and intermolecular H-bonding networks by SLs in biological systems. The C4=C5 double bond can act as a weak H-bond acceptor that allows the tethering of one or more water molecules. Such interactions extend the interfacial region of SLs, which clearly can affect their packing in the lipid bilayer arrangement. Besides, the presence of such additional potential binding site and the floppiness of the possible πH bond can be critical for the molecular recognition of SL second messengers in signaling pathways and may account for the diminished biological activity of saturated SL analogs. |
