Building Synthetic Sterols Computationally - Unlocking the Secrets of Evolution?

Abstract

Cholesterol is vital in regulating the physical properties of animal cell membranes. While it remains unclear what renders cholesterol so unique, it is known that other sterols are less capable in modulating membrane properties, and there are membrane proteins whose function is dependent on cholesterol. Practical applications of cholesterol include its use in liposomes in drug delivery and cosmetics, cholesterol-based detergents in membrane protein crystallography, its fluorescent analogs in studies of cholesterol transport in cells and tissues, etc. Clearly, in spite of their difficult synthesis, producing the synthetic analogs of cholesterol is of great commercial and scientific interest. In this article, we discuss how synthetic sterols non-existent in nature can be used to elucidate the roles of cholesterol's structural elements. To this end, we discuss recent atomistic molecular dynamics simulation studies that have predicted new synthetic sterols with properties comparable to those of cholesterol. We also discuss more recent experimental studies that have vindicated these predictions. The paper highlights the strength of computational simulations in making predictions for synthetic biology, thereby guiding experiments.

Keywords: cholesterol; computer simulation; molecular dynamics simulation; synthetic sterol.

Figure 1

Structures of (A) lanosterol, (B) cholesterol, and (C) Dchol. Chemical structures and atom numberings are shown on the left. The sites where differences occur between lanosterol and cholesterol have been colored with pink, and the methyl groups that are removed in Dchol are marked in yellow. In the middle and on the right, space-filling models of the same molecules are given. The middle panel shows only the ring system of each sterol. The point of view is from the direction of the hydroxyl group, and the ring system lies on the perpendicular plane. The off-plane methyl groups are colored in orange, and carbons in cyan. On the right, space-filling models of the whole sterol molecules are shown as side views, the ring system lying on the horizontal plane. The off-plane methyl groups are colored in orange, carbons in cyan, oxygen in red, and hydrogen in silver.

Figure 2

Sterol–sterol in-plane distribution and configurations of sterol molecules in a DSPC bilayer with 20 mol% sterol. Two-dimensional density distribution for the ring atoms of (A) cholesterol around a tagged cholesterol and (B) Dchol around a tagged Dchol. Both (A,B) show a schematic representation of the tagged sterol (see also Figure 1). The β-face of cholesterol is divided into two sub-faces: β₁ and β₂. (A) shows that cholesterols avoid the first coordination shell, instead forming a clear second coordination shell. The three emerging peaks, each on a different face, are marked with blue arrows. (B) shows that the two sides of Dchol behave in a similar manner as the smooth α-face of cholesterol. No Dchol is seen in the first coordination shell, and peaks (marked with blue arrows) are observed on both faces. Some structure is still visible in the outer coordination shell around 1.8 nm. Two peaks, which are collinear with the previous ones, are marked with green arrows. This reflects a strong preference to form linear Dchol–Dchol structures. (C,D) show a top view of an equilibrated configuration of (C) a DSPC/cholesterol bilayer and (D) a DSPC/Dchol bilayer. Only one leaflet is drawn for clarity. PC molecules are shown as black sticks and sterols with a red space-filling model. The boundary of the simulation box is marked with the green square and color brightness. (C) shows the connections between neighboring cholesterol molecules forming triangular patterns, whereas in (D), the connection patterns formed by Dchol molecules are clearly linear. This fundamental difference is due to the missing out-of-plane methyl groups in the Dchol molecule. Figure adapted from Martinez-Seara et al. (2010).