2006

Abstract:
Sterols constitute a large family of chemical species. Yet only cholesterol and ergosterol are found in substantial amounts in nature. Cholesterol concentration in cell membranes is usually about 30 mol%, though in red blood cells it may reach 50 mol% and in ocular lens membranes even 70 mol%. The biological roles of Chol involve maintenance of proper fluidity, formation of glycosphingolipid-Chol-enriched raft domains, reduction of passive permeability, and increasing the mechanical strength of the membrane. The cholesterol molecule consists of a planar tetracyclic ring system with the 3beta-hydroxyl group and a short 8-carbon chain. The ring system is asymmetric about the ring plane, and has a flat side with no substituents (alpha-face) as well as a rough side with two methyl groups (beta-face). Being a smooth and rigid molecule, cholesterol is known to increase the order of saturated acyl chains of phospholipids and the membrane surface density. A variety of cholesterol analogues, on the other hand, have been reported to have a much weaker effect on membrane ordering and condensation.

To understand these specific requirements for the sterol structure, molecular dynamics simulations of lipid bilayers composed of saturated and unsaturated phosphatidylcholines and selected sterols were performed. Among the studied sterols were cholesterol, epicholesterol, ketosterol, desmosterol, 7-dehydrocholesterol, and a sterol with methyl groups removed from the beta-face. These studies into the effect of sterol structure on lipid bilayer properties allow us to select factors responsible for the strength of sterol effects on bilayer properties. Among them are: sterol tilt, vertical location of hydroxyl group and sterol smoothness. The reason for changes in the sterol tilt or its vertical location can have different molecular origins like different van der Waals interactions between altered sterol parts and lipids or modified hydrogen bonding patterns.

References:

1. M. Pasenkiewicz-Gierula, T.Rog, K. Kitamura, A. Kusumi. 2000. Cholesterol effects on the phosphatidylcholine bilayer polar region: a molecular simulation study. Biophys. J. 78:1376-1389
2. T.Rog, M. Pasenkiewicz-Gierula. 2001. Cholesterol effects on the pchosphatidylcholine bilayer nonpolar region: a molecular simulation study. Biophys. J. 81:2190-2202.
3. T.Rog, M. Pasenkiewicz-Gierula. 2001. Cholesterol effect on the phospholipid condensation and packing in the bilayer: a molecular simulation study. FEBS Letters. 502:68-71
4. T.Rog, M. Pasenkiewicz-Gierula. 2003. Comparison of effects of epicholesterol and cholesterol on the phosphatidylcholine bilayer: a molecular dynamics simulation study. Biophys. J. 84:1818-1826
5. T.Rog, M. Pasenkiewicz-Gierula. 2004. Cholesterol-phospholipid hydrophobic interactions: a molecular simulation study. Biophys. Chem. 107:151-164
6. S. Vainio, M. Jansen, M. Koivusalo, T.Rog, M. Karttunen, I. Vattulainen, E. Ikonen. Desmosterol cannot replace cholesterol in lipid rafts. J. Biol. Chem. 281:348-355
7. T.Rog, M. Pasenkiewicz-Gierula. 2006. Cholesterol-sphingomieline interactions: a molecular dynamics simulation study. Biophys. J. doi:10.1529/biophysj.106.080887
8. J. Aittoniemi, T.Rog, P. NiemelŠ, M. Pasenkiewicz-Gierula, M. Karttunen, I. Vattulainen. How sterol structure determines sterol action in lipid membranes. Submitted.
9. T.Rog, I. Vattulainen, M. Pasenkiewicz-Gierula, M. Karttunen. What happens if cholesterol is made smoother: Importance of methyl substituents in cholesterol ring structure on phosphatidylcholineÐsterol interaction? Submitted.
10. S. Ollila, T.Rog, M. Karttunen, I. Vattulainen. Role of sterol type on lateral profiles of lipid membranes affecting membrane protein functionality: comparison between cholesterol, desmosterol, 7-dehydrocholesterol and ketosterol. Submitted