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Lateral Diffusion of Phospholipids M...

Lai, Angel.

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Lateral Diffusion of Phospholipids Measured Using 31 P Solid State CODEX NMR.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Lateral Diffusion of Phospholipids Measured Using 31 P Solid State CODEX NMR./
Author:	Lai, Angel.
Published:	Ann Arbor : ProQuest Dissertations & Theses, : 2018,
Description:	178 p.
Notes:	Source: Dissertations Abstracts International, Volume: 80-01, Section: B.
Contained By:	Dissertations Abstracts International80-01B.
Subject:	Chemistry. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=10791160
ISBN:	9780438188273

Lateral Diffusion of Phospholipids Measured Using 31 P Solid State CODEX NMR.
Lai, Angel.

Lateral Diffusion of Phospholipids Measured Using 31 P Solid State CODEX NMR. - Ann Arbor : ProQuest Dissertations & Theses, 2018 - 178 p.

Source: Dissertations Abstracts International, Volume: 80-01, Section: B.

Thesis (Ph.D.)--University of Toronto (Canada), 2018.

This item must not be sold to any third party vendors.

Lateral diffusion of phospholipids is a process essential to membrane function, and its accurate determination can provide insights into the kinetics of many membrane-associated biochemical reactions. This thesis focuses on using 31P CODEX NMR to measure phospholipid lateral diffusion. A powder-average model was developed to extract phospholipid lateral diffusion coefficients from 31P CODEX NMR data, starting with theory, numerical simulations, and finally experimental data fitting. The synthesis of large, unilamellar vesicles and the CODEX experiment were both optimized for this type of measurement. This method was demonstrated to provide lateral diffusion coefficients for phospholipids in both liquid-crystalline and gel phases consistent with established literature values. This model was then used to probe electrostatic interactions between the cationic polyelectrolyte poly-lysine and various anionic phospholipids. Each species of phospholipid will have a different phosphate head group, which will appear as separate narrow resonances in a 31P CODEX spectrum. This property allows for simultaneous monitoring of each diffusing species and a simple measurement of any selectivity in the electrostatic interactions. The addition of poly-lysine to anionic liposomes proved to have a minimal effect in liposomes composed of POPG, DOPS, and TOCL, but created electrostatically-induced domains in liposomes containing DOPA. This method could prove useful in studying other electrostatic interactions between the membrane bilayer and surface-binding proteins or drugs. Lastly, the membrane-disrupting mechanism of an antimicrobial peptide KL-14 was examined. Permeability assays were conducted to probe KL-14's efficacy in various membrane compositions. Phospholipid selectivity was also investigated using 31P static and 31P CODEX NMR under MAS. In conjunction, these studies can create a more complete mechanism for this class of peptide. Three of the main types of membrane-disrupting mechanisms for this type of peptide in literature were eliminated based on experimental data, namely the barrel-stave, toroidal pore, and aggregate models. The carpet model is the remaining prevalent proposed model and could not be completely ruled out based on the data obtained in these studies, and thus remains a possibility. A better understanding of how antimicrobial peptides cause membrane disruption will aid in better rational design of therapeutics in combating the rise of antibiotic resistance.

ISBN: 9780438188273Subjects--Topical Terms:

516420
Chemistry.
Subjects--Index Terms:

Antimicrobial peptide

Lateral Diffusion of Phospholipids Measured Using 31 P Solid State CODEX NMR.
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245 1 0 $a Lateral Diffusion of Phospholipids Measured Using 31 P Solid State CODEX NMR.
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300 $a 178 p.
500 $a Source: Dissertations Abstracts International, Volume: 80-01, Section: B.
500 $a Publisher info.: Dissertation/Thesis.
500 $a Advisor: Macdonald, Peter M.
502 $a Thesis (Ph.D.)--University of Toronto (Canada), 2018.
506 $a This item must not be sold to any third party vendors.
520 $a Lateral diffusion of phospholipids is a process essential to membrane function, and its accurate determination can provide insights into the kinetics of many membrane-associated biochemical reactions. This thesis focuses on using 31P CODEX NMR to measure phospholipid lateral diffusion. A powder-average model was developed to extract phospholipid lateral diffusion coefficients from 31P CODEX NMR data, starting with theory, numerical simulations, and finally experimental data fitting. The synthesis of large, unilamellar vesicles and the CODEX experiment were both optimized for this type of measurement. This method was demonstrated to provide lateral diffusion coefficients for phospholipids in both liquid-crystalline and gel phases consistent with established literature values. This model was then used to probe electrostatic interactions between the cationic polyelectrolyte poly-lysine and various anionic phospholipids. Each species of phospholipid will have a different phosphate head group, which will appear as separate narrow resonances in a 31P CODEX spectrum. This property allows for simultaneous monitoring of each diffusing species and a simple measurement of any selectivity in the electrostatic interactions. The addition of poly-lysine to anionic liposomes proved to have a minimal effect in liposomes composed of POPG, DOPS, and TOCL, but created electrostatically-induced domains in liposomes containing DOPA. This method could prove useful in studying other electrostatic interactions between the membrane bilayer and surface-binding proteins or drugs. Lastly, the membrane-disrupting mechanism of an antimicrobial peptide KL-14 was examined. Permeability assays were conducted to probe KL-14's efficacy in various membrane compositions. Phospholipid selectivity was also investigated using 31P static and 31P CODEX NMR under MAS. In conjunction, these studies can create a more complete mechanism for this class of peptide. Three of the main types of membrane-disrupting mechanisms for this type of peptide in literature were eliminated based on experimental data, namely the barrel-stave, toroidal pore, and aggregate models. The carpet model is the remaining prevalent proposed model and could not be completely ruled out based on the data obtained in these studies, and thus remains a possibility. A better understanding of how antimicrobial peptides cause membrane disruption will aid in better rational design of therapeutics in combating the rise of antibiotic resistance.
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653 $a Membrane
653 $a Poly lysine
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