Cholesterol Flip-Flop Impacts Domain Registration in Plasma Membrane Models

Abstract

The plasma membrane is a highly complex multicomponent system that is central to the functioning of cells. Cholesterol, a key lipid component of the plasma membrane, promotes the formation of nanodomains. These nanodomains are often correlated across the two membrane leaflets, but the underlying physical mechanism remains unclear. Using coarse-grained molecular dynamics simulations, we investigate the influence of cholesterol flip-flop on membrane properties, in particular, the interleaflet coupling of cholesterol-enriched domains. We show that the cholesterol density correlation between the leaflets of an average mammalian plasma membrane is significantly reduced by suppressing interleaflet cholesterol population. Our results suggest an amplifying role of cholesterol in signal transduction across the leaflets.

Lateral heterogeneity and domain formation in cellular membranes

“…It was observed that cholesterol resided near the bilayer center in thinner membranes, such as those made up of highly disordered lipids, e.g., PUFAs ( Kučerka et al, 2010 , Marrink et al, 2008 , Harroun et al, 2006 , Harroun et al, 2008 ). This is in contrast to what has been observed in membranes comprised of ordered lipids, such as sphingomyelin, where cholesterol resides closer to the aqueous surface and is less dynamic ( Thallmair et al, 2018 ). The entropic difference between these two states results in a tension at domain boundaries ( Thallmair et al, 2018 , Weiner and Feigenson, 2018 ) (see Fig.…”

“…(b) Cholesterol (yellow) may also play a role in domain coalescence. In the case of thinner domains (red), cholesterol resides closer to the bilayer center and results in entropically unfavorable interactions (light blue highlights) when near ordered domains (blue) or at domain boundaries (adapted from Thallmair et al( Thallmair et al, 2018 )). (c) Further, cholesterol experiences unfavorable packing conditions when near unsaturated and methylated lipids, which can drive the sterol toward ordered domains, increasing the possibility of domain formation.…”

Real-time cholesterol sorting in Plasmodium falciparum-erythrocytes as revealed by 3D label-free imaging

“…In eukaryotic cells, intracellular lipid transport utilizes vesicle transport (COP I transport vesicles) 10 and non-vesicle transport systems (e.g., flip-flop 11,12 , lateral exchange 13,14 , and lipid transfer proteins 15 ). Cholesterol, an essential lipid for eukaryotic cells, is typically sorted in the endoplasmic reticulum and is sent to organelles and plasma membranes [16][17][18] .…”

Recent Advances in Coarse-Grained Models for Biomolecules and Their Applications

“…Therefore, the model for activation of immune receptors in the membrane environment was proposed. The MARTINI model has also been used to study the role of cholesterol in the domain registration in plasma membrane [78]. Recently, Hirano et al reported the MARTINI force field parameters for an ATP molecule and applied it to study ATP-induced dimerization of nucleotide binding domains of maltose transporter [42].…”