Molecular origins of bending rigidity in lipids with isolated and conjugated double bonds: The effect of cholesterol

We examine the effects of cholesterol (Chol) on the mechanical properties of membranes consisting of 16:0/18:1 POPC lipid and of lipids with conjugated linoleic acid (CLA), cis-9/trans-11 CLA (C9T11) and trans-10/cis-12 CLA (T10C12). Atomistic molecular dynamics (MD) simulations of POPC-Chol and CLA-Chol mixtures at various Chol concentrations are employed within a recently developed and validated computational methodology (Khelashvili et al., 2013) that calculates from MD trajectories the bending rigidity (K_C) for these systems. We have found that the addition of 30% Chol stiffens POPC lipid membranes much more significantly (2.3-fold) than it does C9T11 (1.5-fold) or T10C12 (1.75-fold) lipid bilayers. Extensive comparative structural analysis of the simulated mixtures supports a molecular mechanism for the differential effects of cholesterol, whereby the sterol molecules tilt more significantly in CLA membranes where they also insert deeper inside the hydrocarbon core. The observed distinct arrangement of Chol molecules in CLA and POPC bilayers, in turn, is dictated by the interplay between the specific location of the trans double bond in the two CLA lipid isomers and the preferential interaction of the rigid Chol ring with the saturated segments of the lipid tails. The simulations and analysis described in this paper provide novel insights into the specific modes of molecular interaction in bilayers composed of mixtures of Chol and unsaturated lipids that drive emergent macroscopic properties, such as the membrane's bending modulus.