LIPID FORCE FIELD PARAMETERIZATION FOR IMPROVED MODELING OF ION-LIPID INTERACTIONS AND ETHER LIPIDS, AND EVALUATION OF THE EFFECTS OF LONG-RANGE LENNARD-JONES INTERACTIONS ON ALKANES

Abstract

Chemical specificity of lipid models used in molecular dynamics simulations is essential to accurately represent the complexity and diversity of biological membranes. This dissertation discusses contributions to the CHARMM36 (C36) family of lipid force fields, including a revised model for the glycerol-ether linkage found in plasmalogens and archaeal membranes; interaction parameters between ions and lipid oxygens; and evaluation of the effects of long-range Lennard-Jones parameters on alkanes.

Long-range Lennard-Jones interactions have a significant impact on structural and thermodynamic properties of systems with nonpolar regions such as membranes. Effects of these interactions on properties of alkanes are investigated. Implementation of the Lennard-Jones particle-mesh Ewald (LJ-PME) method with the C36 additive and Drude polarizable force fields improves agreement with experiment for thermodynamic and kinetic properties of alkanes, with Drude outperforming the additive FF for nearly all quantities. Trends in the temperature dependence of the density and isothermal compressibility are also improved.

Phospholipids containing an ether linkage between the glycerol backbone and hydrophobic tails are prevalent in human red blood cells and nerve tissue. Ab initio results are used to revise linear ether parameters and develop new parameters for the glycerol-ether linkage in lipids. The new force field, called C36e, more accurately represents the dihedral potential energy landscape and improves solution properties of linear ethers. C36e allows more water to penetrate an ether-linked lipid bilayer, increasing the surface area per lipid compared to simulations carried out with the original C36 parameters and improving structural properties.

In addition to modulating membrane structure, lipid-ion interactions influence protein-ligand binding and conformations of membrane-bound proteins. Interaction parameters are introduced describing Be2+ affinity for binding sites on lipids. Experimental binding affinities reveal that Be2+ strongly binds to phosphoryl groups. Revised interaction parameters reproduce binding affinities in solution simulations. In a separate effort, experimental results for the radius of gyration (R_g) of polyethylene glycol (PEG) in various concentrations of KCl reveal that, while C36e parameters reproduce experimental R_g of PEG in the absence of KCl, adding salt results in underestimation of〖 R〗_g. It is found that the water shell around PEG affects R_g calculated from neutron scattering experiments, and K+-PEG interactions increase the gauche character of PEG.