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The Effects of Cholesterol Oxidation on Erythrocyte Plasma Membranes: A Monolayer Study

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Bob Dan Lechner, Paul Smith, Beth McGill, Skye Marshall, Jemma L. Trick, Andrei P. Chumakov, Charles Peter Winlove, Oleg V. Konovalov, Christian D. Lorenz, Peter G. Petrov

Original languageEnglish
Article number828
JournalMembranes
Volume12
Issue number9
DOIs
Accepted/In press18 Aug 2022
PublishedSep 2022

Bibliographical note

Funding Information: Via CDL’s membership of the UK’s HEC Materials Chemistry Consortium, which is funded by EPSRC (EP/L000202/1, EP/R029431/1, EP/T022213), this work used the ARCHER UK National Supercomputing Service (http://www.archer.ac.uk (accessed on 16 August 2022)) and the UK Materials and Molecular Modelling Hub (MMM Hub) for computational resources, which is partially funded by EPSRC (EP/P020194/1, EP/T022213) to carry out the MD simulations reported in this manuscript. PS acknowledges the funding provided by the EPSRC DTP Studentship Block Grant (EP/N509498/1). BMG and SM acknowledge the funding provided by the EPSRC DTP Studentship Block Grant (EP/N509656/1). We acknowledge the European Synchrotron Radiation Facility for granting us beamtime and synchrotron radiation facilities on beamline ID10 under project SC-4816. This work was funded by the EPSRC in the context of the project “Red Cell Physical Properties in Health and Disease” (EP/N007700/1, EP/N007980/1), for which we are grateful. Publisher Copyright: © 2022 by the authors.

King's Authors

Abstract

Cholesterol plays a key role in the molecular and mesoscopic organisation of lipid membranes and it is expected that changes in its molecular structure (e.g., through environmental factors such as oxidative stress) may affect adversely membrane properties and function. In this study, we present evidence that oxidation of cholesterol has significant effects on the mechanical properties, molecular and mesoscopic organisation and lipid–sterol interactions in condensed monolayers composed of the main species found in the inner leaflet of the erythrocyte membrane. Using a combination of experimental methods (static area compressibility, surface dilatational rheology, fluorescence microscopy, and surface sensitive X-ray techniques) and atomistic molecular dynamics simulations, we show that oxidation of cholesterol to 7-ketocholesterol leads to stiffening of the monolayer (under both static and dynamic conditions), significant changes in the monolayer microdomain organisation, disruption in the van der Waals, electrostatic and hydrophobic interactions between the sterol and the other lipid species, and the lipid membrane hydration. Surface sensitive X-ray techniques reveal that, whilst the molecular packing mode is not significantly affected by cholesterol oxidation in these condensed phases, there are subtle changes in membrane thickness and a significant decrease in the coherence length in monolayers containing 7-ketocholesterol.

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