The influence of hydrophobic mismatch on androsterol/phosphatidylcholine interactions in model membranes.

We have examined the association of 5-androsten-3beta-ol (androsterol) with saturated phosphatidylcholines (PCs), having symmetric acyl chains from 10 to 16 carbons in length, in both mono- and bilayer membranes. The emphasis of the study was to measure how hydrophobic mismatch (i.e. the difference in hydrophobic length of the interacting molecules) affected androsterol/PC interactions in model membranes. With monolayer membranes (33 mol% sterol, 20 mN/m, 25 degreesC), androsterol was found to be macroscopically miscible with all the tested PCs. Androsterol was observed to condense the lateral packing of di14 and di15 PCs (by 6 and 4.5 A2 per molecule, respectively), but failed to condense shorter (di10, di11, di12 and di13 PCs) or the longer chain di16PC. The rate of androsterol desorption from mixed monolayers to beta-cyclodextrin acceptors in the subphase was a clear function of the host PC acyl chain length. The slowest rate of androsterol desorption (i.e. best androsterol/PC interaction) was seen from a di14PC monolayer, whereas the desorption rate increased when the host PC had shorter or longer chains. When the cholesterol oxidase susceptibility of androsterol was determined in small unilamellar vesicles (SUV) containing PCs of different chain lengths (33 mol% androsterol), the slowest rate of oxidation was seen in di14PC vesicles, whereas higher rates were measured for shorter or longer chain PC vesicles, again suggesting that androsterol interacted more favorably with di14PC than with the other PCs. In conclusion, the hydrophobic mismatch between androsterol and different PCs appeared to greatly affect the intermolecular interactions, as determined from the condensation effect, from sterol desorption rates, and the oxidation susceptibility of androsterol. Although androsterol is not a physiological membrane component, the present model system clearly shows that hydrophobic mismatch has a great influence on how sterols and phosphatidylcholines interact in membranes.