Cholesterol’s Condensing Effect: Unpacking a Century-Old Mystery

[Image: see text] The ability of cholesterol to uncoil (i.e., condense) the acyl chains of phospholipids has been known for a century. Despite extensive studies of the interactions between cholesterol and phospholipids, a molecular-level understanding of this uncoiling phenomenon has remained elusive. Equally unclear has been whether cholesterol’s two different faces (i.e., its relatively smooth α face and its relatively rough β face) contribute to its condensing power. Because cholesterol’s condensing effect is believed to play a major role in controlling the fluidity, structure, and functioning of all animal cell membranes, its biological importance cannot be overstated. This Perspective focuses on experimental evidence that addresses (i) the credibility of a popular “umbrella” mechanism that has been used to account for cholesterol’s condensing effect, (ii) the credibility of an alternate “template” mechanism, (iii) the importance of cholesterol two-faced character with respect to its condensing power, and (iv) the viability of a surface occupancy model.