(743f) Extending the CHARMM Force Field to Sphingolipids and Lipids with Polyunsaturated Chains

Biological membranes form a barrier to protect the cell from its environment and consist of a wide variety of lipids.  A recent modification to the CHARMM lipid force field, CHARMM36 (C36), resulted in significant improvements in deuterium order parameters (S_CD), water hydration, and area compressiblities. Moreover, C36 simulations resulted in excellent surface areas per lipid compared to experiment with NPT molecular dynamics (MD). We have extended this force field to several lipids types found in bacteria, but the focus here is the development of parameters for sphingolipids and polyunsaturated lipids.  Sphingolipids contain a fatty acid and a sphingosine chain.  These lipids are common in mammals in various tissues such as the neurons, brain, and ocular lens.  Quantum mechanics was used to develop dihedral potentials of model compounds for the sphingosine.  Non-bonding terms were adjusted to result in NPT MD simulations of sphingomyelin bilayers that match experimental deuterium order parameters (S_CDs) and the correct phase at physiological conditions. With this new class of lipids, future studies on membranes containing ceramides, glycosphingolipids, and gangliosides can be investigated with the CHARMM force field.  Polyunsaturated acyl-chains in lipids with at least two double bonds can drastically alter lipid bilayer properties, such as, head-to-head spacing, surface area per lipid, and cholesterol orientation.  Since parameters for C36 focused on the head group, the CHARMM27 lipid parameters for the polyunsaturated chains were refined to better match structural and dynamical properties of the 1-stearoyl-2-docosahexaenoyl-sn-glycero-3-phosphocholine (SDPC, 18:0/22:6 PC) lipid bilayer.  High-level QM 2-D surfaces about the double bonds were used to fit dihedral parameters.  Consequently, there is an increase in lipid chain disorder that agrees better with the experimental S_CDs.  The updated force field also agrees well with x-ray diffraction and ¹³C NMR relaxation time measurements.