Structure and Dynamics of Biomembranes containing Cholesterol and other Biologically-Important Sterols : a computational perspective

In this thesis, the differential effects of three closely-related sterols: ergosterol, cholesterol and lanosterol on the structural and dynamical properties of a model dipalmitoyl phosphatidylcholine (DPPC) membrane were examined using Molecular Dynamics (MD) simulations and Neutron Scattering (NS) calculations. As a necessary step towards realistic sterol:biomembrane simulations, molecular mechanics force field parameters for cholesterol, ergosterol and lanosterol, for the program package CHARMM are derived. Subsequently, MD simulations of hydrated sterol:DPPC lipid systems are performed at a biologically-relevant concentration (40\% mol.) at 309K and 323K. The simulations are compared with control simulations of the gel and liquid DPPC phases. All three sterols are found to order and condense the lipids relative to the liquid phase, but to markedly different degrees. Ergosterol is enhancing the packing of the lipids with each other and has a higher condensing effect on the membrane than the other two sterols. Moreover, ergosterol induces a higher proportion of trans lipid conformers, a thicker membrane and higher lipid order parameters, and is aligned more closely with the membrane normal. Ergosterol also positions itself closer to the bilayer:water interface. In contrast, lanosterol orders, straightens and packs the lipids less well, and is less closely aligned with the membrane normal. Furthermore, lanosterol lies closer to the relatively-disordered membrane center than do the other sterols. The behaviour of cholesterol in all the above respects is intermediate between that of lanosterol and ergosterol. The origins of the different membrane behavior upon addition of each sterol are discussed with respect to the sterol chemical differences. Ergosterol was also found to diffuse the slowest and cholesterol the fastest both in the xy-plane and the z-axis of the membrane among the three sterols studied. The findings here may explain why ergosterol is the most efficient of the three sterols at promoting the liquid-ordered phase and lipid domain formation, and may also furnish part of the explanation as to why cholesterol is evolutionarily preferred over lanosterol in higher-vertebrate plasma membranes