Cholesterol-induced suppression of membrane elastic fluctuations at the atomistic level

Abstract

Applications of solid-state NMR spectroscopy for investigating the influences of lipid-cholesterol interactions on membrane fluctuations are reviewed in this paper. Emphasis is placed on understanding the energy landscapes and fluctuations at an emergent atomistic level. Solid-state 2H NMR spectroscopy directly measures residual quadrupolar couplings (RQCs) due to individual C–2H labeled segments of the lipid molecules. Moreover, residual dipolar couplings (RDCs) of 13C–1H bonds are obtained in separated local-field NMR spectroscopy. The distributions of RQC or RDC values give nearly complete profiles of the order parameters as a function of acyl segment position. Measured equilibrium properties of glycerophospholipids and sphingolipids including their binary and tertiary mixtures with cholesterol show unequal mixing associated with liquid-ordered domains. The entropic loss upon addition of cholesterol to sphingolipids is less than for glycerophospholipids and may drive the formation of lipid rafts. In addition relaxation time measurements enable one to study the molecular dynamics over a wide time-scale range. For 2H NMR the experimental spin-lattice (R1Z) relaxation rates follow a theoretical square-law dependence on segmental order parameters (SCD) due to collective slow dynamics over mesoscopic length scales. The functional dependence for the liquid-crystalline lipid membranes is indicative of viscoelastic properties as they emerge from atomistic-level interactions. A striking decrease in square-law slope upon addition of cholesterol denotes stiffening relative to the pure lipid bilayers that is diminished in the case of lanosterol. Measured equilibrium properties and relaxation rates infer opposite influences of cholesterol and detergents on collective dynamics and elasticity at an atomistic scale that potentially affects lipid raft formation in cellular membranes.

How cholesterol stiffens unsaturated lipid membranes

“…The correlated increase in membrane viscosity and bending rigidity is in line with the effect of Chol on local viscoelastic membrane properties and its molecularlevel suppression of elastic fluctuations. This result was shown both in NSE studies of POPC membranes (29) and in solid-state 2 H NMR experiments of DMPC-d 54 membranes (19,48).…”

Soft Matter in Lipid–Protein Interactions

“…A molecular-level understanding of the forces acting on lipids and proteins in membranes rests on knowledge of pure bilayer dynamics and thermodynamics in the absence of complicating protein molecules. For example, nuclear magnetic resonance (NMR) spectroscopy provides knowledge of average structure (142) and lipid mobility (27,95), and has been applied to investigate the influences of ions (25,141), water (84), cholesterol (1,26,106,114,161), and proteins (15,152). Segmental order parameters of the lipids are directly accessible (95), as interpreted by Seelig (142) and others (44,128) in terms of local bilayer structure and dynamics (27).…”

“…modes emerge on the mesoscale of the bilayer thickness and less as a result of the bulk membrane elasticity; yet the bilayer core resembles a simple hydrocarbon fluid (18,95). Cholesterol yields increased bilayer stiffness and dampens the quasielastic membrane excitations at an atomistic level (106,114), where its effects on lipid miscibility underlie nanoscale heterogeneities or inclusions with proteins known as rafts (1,144,161).…”

Facilitated and Non-Gaussian Diffusion of Cholesterol in Liquid Ordered Phase Bilayers Depends on the Flip-Flop and Spatial Arrangement of Cholesterol

“…The phase and the diffusion of lipid bilayers depend on both temperature ( T ) and the mole fraction ( x chol ) of cholesterol. ,,− At relatively low temperature and small x chol , lipid bilayers are in the solid (gel) phase, where both lipids and cholesterol hardly diffuse. As T increases, liquid disordered (L d ) phase develops such that both lipids and cholesterol are quite mobile.…”