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

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dc.contributor.advisorKlauda, Jeffery Ben_US
dc.contributor.authorLeonard, Alison Nen_US
dc.contributor.departmentBiophysics (BIPH)en_US
dc.contributor.publisherDigital Repository at the University of Marylanden_US
dc.contributor.publisherUniversity of Maryland (College Park, Md.)en_US
dc.date.accessioned2019-09-26T05:34:19Z
dc.date.available2019-09-26T05:34:19Z
dc.date.issued2019en_US
dc.description.abstractChemical 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.en_US
dc.identifierhttps://doi.org/10.13016/nzhs-qlt5
dc.identifier.urihttp://hdl.handle.net/1903/24950
dc.language.isoenen_US
dc.subject.pqcontrolledBiophysicsen_US
dc.subject.pqcontrolledBiochemistryen_US
dc.subject.pqcontrolledBiomedical engineeringen_US
dc.subject.pquncontrolledberylliumen_US
dc.subject.pquncontrolledether lipiden_US
dc.subject.pquncontrolledforce fielden_US
dc.subject.pquncontrolledlipidsen_US
dc.subject.pquncontrolledmolecular dynamicsen_US
dc.subject.pquncontrolledpolyethylene glycolen_US
dc.titleLIPID 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 ALKANESen_US
dc.typeDissertationen_US

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