When most people hear the word “cholesterol,” they think about their diet, heart disease, and statins. In fact, cholesterol is also an essential component in the membranes of your cells, the biosynthesis of which evolved in response to the appearance on earth of an oxygen rich atmosphere, roughly two and a half billion years ago.

So what does cholesterol do for your cell membranes? It has been known for many years that cholesterol organizes and orders the fatty acid component of the membrane, leading to a thicker and more tightly packed lipid bilayer. This makes the membrane more effective as a barrier against ions, water, and other small molecules. However, the biophysical details responsible for this behavior have remained largely unknown.

The cover image shows a configuration sampled by a molecular dynamics simulation of a mixture of two lipids and cholesterol, modeled in all-atom detail. The hydrocarbon chains are rendered in red (a sphingolipid) or blue (a monounsaturated phospholipid). Cholesterol is rendered in yellow.  The shapes of the lipids reflect the details of local packing and order. In the more yellow and red region (cholesterol and sphingolipid rich), the chains of the sphingolipid tend to pack tightly into local hexagonal arrays. Though locally hexagonal, this phase is still fluid, and hence referred to as “liquid-ordered.” In the more blue region (richer in unsaturated chains), the lipids are more loosely packed, and are rendered as Voronoi polygons. The corners of the polygons are smoothed by Bezier splines to evoke the softness of the more fluid, “liquid-disordered” phase. The heights of the polygonal solids are the relative heights of the lipids, revealing that the thickening effect of cholesterol is very local. The image was rendered using the Tachyon ray tracing software.

More simulations like this are sure to follow, with ever more complex lipid mixtures. With high-precision models and careful simulation protocols, these efforts will reveal how compositionally complex membrane mixtures conspire to organize for functional ends, such as signaling and trafficking. Whatever is revealed, it is clear that cholesterol will play a leading role.

—Edward Lyman, Alexander Sodt, Richard Pastor