Predicting the effect of steroids on membrane biophysical properties based on the molecular structure

Abstract

The relationship between sterol structure and the resulting effects on membrane physical properties is still unclear, owing to the conflicting results found in the current literature. This study presents a multivariate analysis describing the physical properties of 83 steroid membranes. This first structure-activity analysis supports the generally accepted physical effects of sterols in lipid bilayers. The sterol chemical substituents and the sterol/phospholipid membrane physical properties were encoded by defining binary variables for the presence/absence of those chemical substituents in the polycyclic ring system and physical parameters obtained from phospholipid mixtures containing those sterols. Utilizing Principal Coordinates Analysis, the steroid population was grouped into five well-defined clusters according to their chemical structures. An examination of the membrane activity of each sterol structural cluster revealed that a hydroxyl group at C3 and an 8-10 carbon isoalkyl side-chain at C17 are mainly present in membrane active sterols having rigidifying, molecular ordering/condensing effects and/or a raft promoting ability. In contrast, sterol chemical structures containing a keto group at C3, a C4-C5-double bond, and polar groups or a short alkyl side-chain at C17 (3 to 7 atoms) are mostly found in sterols having opposite effects. Using combined multivariate approaches, it was concluded that the most important structural determinants influencing the physical properties of sterol-containing mixtures were the presence of an 8-10 carbon C17 isoalkyl side-chain, followed by a hydroxyl group at C3 and a C5-C6 double bond. Finally, a simple Logistic Regression model predicting the dependence of membrane activity on sterol chemical structure is proposed.

A DSC and FTIR spectroscopic study of the effects of the epimeric cholestan-3-ols and cholestan-3-one on the thermotropic phase behavior and organization of dipalmitoylphosphatidylcholine bilayer membranes: Comparison with their 5-cholesten analogs

“…However, whether this effect is due the removal of the double bond or to the production of various Chol oxidation products remains to be determined. Whatever its primary role, a recent multivariant analysis of the relationship between sterol structure and their biophysical effects on phospholipid bilayers has found that the presence of a double bond at D 5 is one of the three most important structural features required of the sterol molecule in order to produce its characteristic effects on lipid bilayers, being less important only than a 3b-OH group and an 8-10 C alkyl chain at C17 (Wenz, 2012). Thus, further studies of the molecular basis for this specific structural requirement are warranted.…”

Cholesterol as a co‐solvent and a ligand for membrane proteins

“…At the same time, very small changes in the structure of cholesterol can profoundly alter its properties. For example, reduction of the alkene moiety of cholesterol to generate coprostanol is sufficient to eliminate its ability to promote the formation of raft‐like liquid‐ordered phase domains . The fact that cholesterol is still 18 biochemical steps away from lanosterol (Fig.…”

“…For example, reduction of the alkene moiety of cholesterol to generate coprostanol is sufficient to eliminate its ability to promote the formation of raft-like liquid-ordered phase domains. [12][13][14] The fact that cholesterol is still 18 biochemical steps away from lanosterol ( Fig. 1) belies the high degree to which is has been adapted for a variety of special roles in complex animal forms of life.…”

Influence of the sterol aliphatic side chain on membrane properties: a molecular dynamics study

“…Along these lines, a multivariate analysis of the relationship between the sterol structure and the resulting effects on membrane physical properties revealed that the most important determinants in this respect are, in decreasing order, the presence of an 8-10 carbon C17 isoalkyl side-chain (in opposition to polar groups or a shorter, 3-7 carbon chain), a hydroxyl group at C3 (in contrast to a keto group at this position) and a C5-C6 double bond (rather than a C4-C5 double bond). 21 The latter study highlights the importance of an aliphatic chain of adequate length for optimal molecular packing with membrane phospholipids. In previous work, it was usually assumed that van der Waals interactions between the planar, fused ring system (particularly the smooth a-face) of cholesterol and saturated fatty acyl chains give rise to the favorable interaction of cholesterol with (saturated) phospholipid chains.…”