Moutusi Manna, Sini Mokkila, M. Javanainen
Jan 28, 2014
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Journal
Biophysical Journal
Abstract
Cholesterol is an essential component of the mammalian cell membrane. Thermal fluctuations of cholesterol from its equilibrium position, along the bilayer normal, have important consequences in its cellular trafficking. In this work, we have investigated the effect of replacing part of membrane cholesterol with one of its oxidative products, cholestenone (4-cholesten-3-one, a ketosterone that differs from cholesterol only in the hydroxyl headgroup and the position of double bond), on the transbilayer movement (flip-flop). In the same spirit, we have studied desorption of these sterols from a membrane towards the aqueous phase. The reason why we focus on cholestenone is that it is one of the most common products when cholesterol is being oxidized, thus serving as an example of cholesterol oxidation. The results from our atomistic molecular dynamics simulations show that replacing the hydroxyl group of cholesterol by the keto group found in cholestenone has a significant effect on inter-leaflet translocation of the sterol. To discuss the cause and consequences of the observed effects, we used umbrella (free energy) simulations to calculate the potential of mean force for flip-flop as well as for desorption of these two sterols from the membrane into the water phase. The results brought out that even seemingly tiny changes in sterol structure have considerable implications for sterol dynamics. As cholesterol oxidation is often used to deplete cholesterol in experimental conditions, our results highlight that it is essential to understand the membrane behavior of the introduced lipid species, in this case cholestenone.