Graduation Year

2025

Document Type

Dissertation

Degree

Ph.D.

Degree Name

Doctor of Philosophy (Ph.D.)

Degree Granting Department

Molecular Biosciences

Major Professor

Sameer Varma, Ph.D.

Co-Major Professor

Sagar Pandit, Ph.D.

Committee Member

Jianjun Pan, Ph.D.

Committee Member

Libin Ye, Ph.D.

Committee Member

Stanley Stevens, Ph.D.

Keywords

Molecular Dynamics, Zwitterion, Ion Adsorption, Force-Field, Phospholipid

Abstract

Phospholipids are the main component of cell membranes, providing a delimiting boundary for cells from their environments or from their organelles from the cytosol. Thiscompartmentalization allows cells to maintain quite different solutions within their cells and organelles, including different mixtures dissolved ions. Consequently, these membranes are constantly flanked by complex mixtures of salts at varied concentrations. To study membrane structure, one cannot neglect the contribution of the salts in the local solution. Ions perturb bilayer structure via specific interaction with the phospholipids, primarily with the headgroups. Experimental studies of these systems are somewhat at odds — scattering experiments with different salts and zwitterionic lipids report no significant change in bilayer structure with concentrations as large as 1 M for monovalent ions, and at physiologically relevant concentrations for MgCl2. Groups have reported via headgroup NMR that the headgroup tilt angle is modulated by ion interaction, and thus there must be some adsorption that occurs. Simulations also report thickening of lipid bilayers by ions. Here this discrepancy is addressed by the application of a novel optimization procedure using ab initio substitution energies and associated binding geometries of ions from water to lipid headgroups as targets for model parameter optimization. We apply parameters to replace Lennard–Jones mixing rules. Simulations of NaCl are much more in line with experiments than the mixing rule results. MgCl2 proves more complicated, and herein we propose and characterizetwosetsofparametersthatgivedifferentresults. Wecharacterizetheadsorption modes that Na+, Li+, Mg2+, and Cl- take when adsorbed to a bilayer of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphatidylcholine (POPC), and characterize how these binding modes result in perturbation of the lipid bilayer structure. Experiments are needed to validate the Mg2+ parameters, and several validation targets are provided within.

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