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LIPID-LIPID AND LIPID-DRUG INTERACTIONS IN BIOLOGICAL MEMBRANES
Title
LIPID-LIPID AND LIPID-DRUG INTERACTIONS IN BIOLOGICAL MEMBRANES
Creator
Martynowycz, Michael W.
Date
2016, 2016-07
Description
Interactions between lipids and drug molecules in biological membranes help govern proper biological function in organisms. The mechanisms...
Show moreInteractions between lipids and drug molecules in biological membranes help govern proper biological function in organisms. The mechanisms responsible for hydrophobic drug permeation remain elusive. Many small molecule drugs are hydrophobic. These drugs inhibit proteins in the cellular interior. The rise of antibiotic resistance in bacteria is thought to be caused by mutations in protein structure, changing drug kinetics to favor growth. However, small molecule drugs have been shown to have different mechanisms depending in the structure of the lipid membrane of the target cell. Biological membranes are investigated using Langmuir monolayers at the airliquid interface. These offer the highest level of control in the mimetic system and allow them to be investigated using complementary techniques. Langmuir isotherms and insertion assays are used to determine the area occupied by each lipid in the membrane and the change in area caused by the introduction of a drug molecule, respectively. Specular X-ray re ectivity is used to determine the electron density of the monolayer, and grazing incidence X-ray diffraction is used to determine the inplane order of the monolayer. These methods determine the affinity of the drug and the mechanism of action. Studies are presented on hydrophobic drugs with mammalian membrane mimics using warfarin along with modified analogues, called superwarfarins. Data shows that toxicity of these modified drugs are modulated by the membrane cholesterol content in cells; explaining several previously unexplained effects of the drugs. Membrane mimics of bacteria are investigated along with their interactions with a hydrophobic antibiotic, novobiocin. Data suggests that permeation of the drug is mediated by modifications to the membrane lipids, and completely ceases translocation under certain circumstances.
Ph.D. in Physics, July 2016
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Toward a Comprehensive Atomistic View of Bacterial Outer Membrane Remodeling and Antimicrobial Peptide Susceptibility
Title
Toward a Comprehensive Atomistic View of Bacterial Outer Membrane Remodeling and Antimicrobial Peptide Susceptibility
Creator
Rice, Amy
Date
2019
Description
The cell membrane is arguably one of the most important and complex features of a cell, serving to demarcate “self” from “environment” and...
Show moreThe cell membrane is arguably one of the most important and complex features of a cell, serving to demarcate “self” from “environment” and selectively controlling the flow of material in and out of the cell. Bacterial cell membranes are of additional interest since they serve as the first point of contact for antibiotic drugs or other antimicrobial agents. In this work, I use atomistic molecular dynamics simulations to study factors that alter bacterial susceptibility to antimicrobial agents and their environment, with the goal of better understanding how bacteria are able to modulate their sensitivity.First, I present results from a series of simulations of antimicrobial peptides (AMP) interacting with phospholipid bilayers to elucidate the observed interaction differences between arginine and lysine-containing AMPs. Simulations show that the extensive interaction with arginine is due in part to arginine's strong atomic charge distribution, rather than being purely an effect of the greater hydrogen bond capacity. These results highlight the role of charge and hydrogen bond strength in peptide bilayer insertion, and offer potential insights for designing more potent analogues in the future.Next, the effects of bacterial lipopolysaccharide (LPS) modifications are examined, first to understand study how three key modifications observed in S. enterica affect bilayer properties, as well as to examine the role these modifications play in AMP resistance. We hypothesize that defects at the crystalline/liquid-ordered boundary facilitate LL-37 intercalation into the outer membrane, whereas LPS modification protects against this process by having already increased crystallinity and packing efficiency. These results further improve our understanding of outer membrane chemical properties and help elucidate how outer membrane modification systems are able to alter bacterial virulence and susceptibility. Lastly, I investigate the effects of ion type and phosphate charge on four distinct LPS types. Simulations show that bilayer properties are highly influenced by the choice of cation type, ion parameterization, and phosphate group charges. Additional free energy perturbation simulations predict that the protonated LPS state should dominate at physiological pH, in contrast to the deprotonated state utilized by many LPS force fields. Overall, these results reveal inaccuracies in the existing LPS force fields and establish guidelines to better reproduce experimental LPS membrane properties.
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