TY - JOUR

T1 - Long chain sphingomyelin depletes cholesterol from the cytoplasmic leaflet in asymmetric lipid membranes

AU - Karlsen, Maria Lyngby

AU - Bruhn, Dennis S.

AU - Pezeshkian, Weria

AU - Khandelia, Himanshu

PY - 2021/7/8

Y1 - 2021/7/8

N2 - The transbilayer distribution of cholesterol (CHL) in complex asymmetric lipid membranes remains controversial, with contrasting investigations suggesting that there is more CHL either in the exoplasmic, outer leaflet (OL) or the cytoplasmic, inner leaflet (IL) depending on cell type or model, membrane composition, and method of investigation. Here, we launch systematic coarse-grained molecular dynamics simulations to investigate the impact of the sphingomyelin (SM) acyl chain length upon CHL distribution in asymmetric lipid membrane mixtures which account for the variation of the most abundant headgroups and acyl chain unsaturation in the two membrane leaflets. We find that there is always more CHL in the OL, but longer chain SM depletes more CHL from the IL than short chain SM in simple membrane mixtures containing SM and 16 : 0, 18 : 1 phospholipids. The difference between longer and shorter chain SM is neutralised in a more complex asymmetric membrane, where there are more saturated tails in the outer leaflet. We propose that interdigitation of long-chain SM into the opposing IL pushes cytoplasmic CHL towards the OL, but higher chain saturation of the outer leaflet compensates for the effect of SM chain length.

AB - The transbilayer distribution of cholesterol (CHL) in complex asymmetric lipid membranes remains controversial, with contrasting investigations suggesting that there is more CHL either in the exoplasmic, outer leaflet (OL) or the cytoplasmic, inner leaflet (IL) depending on cell type or model, membrane composition, and method of investigation. Here, we launch systematic coarse-grained molecular dynamics simulations to investigate the impact of the sphingomyelin (SM) acyl chain length upon CHL distribution in asymmetric lipid membrane mixtures which account for the variation of the most abundant headgroups and acyl chain unsaturation in the two membrane leaflets. We find that there is always more CHL in the OL, but longer chain SM depletes more CHL from the IL than short chain SM in simple membrane mixtures containing SM and 16 : 0, 18 : 1 phospholipids. The difference between longer and shorter chain SM is neutralised in a more complex asymmetric membrane, where there are more saturated tails in the outer leaflet. We propose that interdigitation of long-chain SM into the opposing IL pushes cytoplasmic CHL towards the OL, but higher chain saturation of the outer leaflet compensates for the effect of SM chain length.

KW - COARSE-GRAINED MODEL

KW - MOLECULAR-DYNAMICS

KW - ORGANIZATION

KW - GROMACS

U2 - 10.1039/d1ra01464a

DO - 10.1039/d1ra01464a

M3 - Journal article

C2 - 35480443

VL - 11

SP - 22677

EP - 22682

JO - RSC Advances

JF - RSC Advances

SN - 2046-2069

IS - 37

ER -