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Fate of liposomes in presence of phospholipase C and D: from atomic to supramolecular lipid arrangement

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Title: Fate of liposomes in presence of phospholipase C and D: from atomic to supramolecular lipid arrangement
Authors: Holme, MN
Rashid, MH
Thomas, MR
Barriga, HMG
Herpoldt, KL
Heenan, RK
Dreiss, CA
Banuelos, JL
Xie, HN
Yarovsky, I
Stevens, MM
Item Type: Journal Article
Abstract: Understanding the origins of lipid membrane bilayer rearrangement in response to external stimuli is an essential component of cell biology and the bottom-up design of liposomes for biomedical applications. The enzymes phospholipase C and D (PLC and PLD) both cleave the phosphorus–oxygen bonds of phosphate esters in phosphatidylcholine (PC) lipids. The atomic position of this hydrolysis reaction has huge implications for the stability of PC-containing self-assembled structures, such as the cell wall and lipid-based vesicle drug delivery vectors. While PLC converts PC to diacylglycerol (DAG), the interaction of PC with PLD produces phosphatidic acid (PA). Here we present a combination of small-angle scattering data and all-atom molecular dynamics simulations, providing insights into the effects of atomic-scale reorganization on the supramolecular assembly of PC membrane bilayers upon enzyme-mediated incorporation of DAG or PA. We observed that PC liposomes completely disintegrate in the presence of PLC, as conversion of PC to DAG progresses. At lower concentrations, DAG molecules within fluid PC bilayers form hydrogen bonds with backbone carbonyl oxygens in neighboring PC molecules and burrow into the hydrophobic region. This leads initially to membrane thinning followed by a swelling of the lamellar phase with increased DAG. At higher DAG concentrations, localized membrane tension causes a change in lipid phase from lamellar to the hexagonal and micellar cubic phases. Molecular dynamics simulations show that this destabilization is also caused in part by the decreased ability of DAG-containing PC membranes to coordinate sodium ions. Conversely, PLD-treated PC liposomes remain stable up to extremely high conversions to PA. Here, the negatively charged PA headgroup attracts significant amounts of sodium ions from the bulk solution to the membrane surface, leading to a swelling of the coordinated water layer. These findings are a vital step toward a fundamental understanding of the degradation behavior of PC lipid membranes in the presence of these clinically relevant enzymes, and toward the rational design of diagnostic and drug delivery technologies for phospholipase-dysregulation-based diseases.
Issue Date: 22-Aug-2018
Date of Acceptance: 10-Jul-2018
URI: http://hdl.handle.net/10044/1/62566
DOI: https://dx.doi.org/10.1021/acscentsci.8b00286
ISSN: 2374-7943
Publisher: American Chemical Society
Start Page: 1023
End Page: 1030
Journal / Book Title: ACS Central Science
Volume: 4
Issue: 8
Copyright Statement: © 2018 American Chemical Society. This is an open access article published under a Creative Commons Attribution (CC-BY) License, which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited.
Sponsor/Funder: Engineering & Physical Science Research Council (E
Engineering & Physical Science Research Council (EPSRC)
Commission of the European Communities
Commission of the European Communities
Funder's Grant Number: EP/K031953/1
EP/K020641/1
ERC-2013-CoG-616417
PIEF-GA-2013-626766
Keywords: Science & Technology
Physical Sciences
Chemistry, Multidisciplinary
Chemistry
PHASE-BEHAVIOR
PORE-FORMATION
PHOSPHATIDYLCHOLINE
BILAYER
CANCER
ASSAY
SIMULATIONS
MEMBRANE
DIACYLGLYCEROLS
DISORDERS
Publication Status: Published
Open Access location: https://pubs.acs.org/doi/10.1021/acscentsci.8b00286
Online Publication Date: 2018-08-06
Appears in Collections:Faculty of Engineering
Materials
Faculty of Natural Sciences



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