Cholesterol stiffening of lipid membranes and drug interactions: Insights from neutron spin echo and deuterium NMR spectroscopy

Biological cell membranes are responsible for a range of phenomena that are critical to cellular functions. Cholesterol, a key component of mammalian cell membranes, controls membrane order, dynamics, and other essential physicochemical parameters. However, reports on the mechanical effects of cholesterol present an enigma to understanding membrane structure-property relations and its role in membrane functions. Specifically, cholesterol exhibits a densification effect on fluid lipid membranes, but it is assumed to have nonuniversal effects on membrane bending rigidity—cholesterol stiffens saturated lipid membranes but has no stiffening effect on membranes with di-monounsaturated lipids. Utilizing a combination of neutron spin echo spectroscopy (NSE), solid-state deuterium NMR spectroscopy, and molecular dynamics simulations, we show that cholesterol locally increases the bending rigidity of unsaturated lipid membranes, like saturated membranes, through changes to molecular packing. These observations have direct implications in the role of cholesterol in drug uptake and drug delivery applications.