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Cholesterol is so essential to the proper function of mammalian cell membranes that even strikingly small inborn errors in cholesterol synthesis can be devastating. Here we combine molecular dynamics simulations with small angle x-ray diffraction experiments to compare mixed sterol/DMPC membranes over a wide range of sterol compositions for two types of sterols: cholesterol and its immediate metabolic precursor 7DHC, that differs from cholesterol by one double bond. We find that while most membrane properties are only slightly affected by the replacement of one sterol by the other, the tilt degree of freedom, as gauged by the tilt modulus, is significantly larger for cholesterol than for 7DHC over a large range of concentrations. In silico mutations of one sterol into the other further support these findings. Moreover, bending rigidities calculated from simulations and estimated in experiments show that cholesterol stiffens membranes to a larger extent than 7DHC. We discuss the possible mechanistic link between sterol tilt and the way it impacts the membrane mechanical properties, and comment on how this link may shed light on the way replacement of cholesterol by 7DHC leads to disease.

Impact of sterol tilt on membrane bending rigidity in cholesterol and 7DHC-containing DMPC membranes