Biological membranes segregate cells and organelles, act as barriers for the passive transport of matter, and support a wide range of important metabolic processes, including active transport, energy flow, signal transduction, and motility. The two main components of membranes are lipids and proteins. Depending on the type of membrane, lipids contribute between 20 and 80% by weight to the total membrane mass, the rest being protein. The lipid molecules are predominantly arranged in a bilayer structure with the hydrophilic head groups facing the aqueous environments and the fatty acyl chains forming the inner hydrophobic core. Minor but functionally important components of membranes are carbohydrates. They are covalently attached to either lipids (glycolipids) or proteins (glycoproteins) and are restricted to the outer leaflet of the bilayer membrane.
The distribution of the lipids between the inner and outer leaflet of a biological membrane is asymmetric, with the outer surface being enriched in phosphatidyl-choline (PC) and the inner, cytosolic surface in phos-phatidylethanolamine (PE) and phosphatidylserine (PS). As a result, the outer lipid membrane surface is electrically neutral and the inner negatively charged. Spontaneous randomization (flip-flop) of zwitterionic lipids between the two leaflets is extremely slow. Specific transport proteins, belonging to the adenosine triphosphate (ATP) binding cassette, further maintain lipid asymmetry. Lipid asymmetry may play a role for the proper orientation of membrane proteins.
The lipid composition of natural membranes is quite heterogeneous. The large variability with respect to head groups, chain length, and extent of cis-unsaturation results in thousands of chemically different lipids. For example, the membrane of the red blood cell contains about 400 chemically different lipids. The lipid composition and the lipid-to-protein ratio of a given membrane are relatively well defined, suggesting a correlation between lipid composition and membrane function. At present, little is known of how the lipid composition is controlled and why biological membranes contain so many different lipids. Many biological membranes can adapt to changing external conditions such as temperature or long-term exposure to drugs or alcohol by modifying their lipid composition in order to maintain the optimal conditions for cell growth.
Hydrophobic membrane proteins and lipids are difficult to crystallize compared to water-soluble biological molecules. Consequently, structural information on membrane components has become available at a much slower pace than on water-soluble proteins or DNA.
The situation is even worse for membrane lipids. Not a single, naturally occurring phospholipid with unsaturated hydrocarbon chains has yet been crystallized. However, nearly 40 crystal structures of closely related synthetic glycerolipids with saturated hydrocarbon chains have been solved by X-ray. On the structural level, little is known about the interactions of proteins with lipid bilayer environments. Detergent molecules have been detected in some of the X-ray structures, and a small number of studies discuss lipids bound to proteins. An example is cy-tochrome C oxidase crystals, where the lipids were found to be arranged in a bilayer structure.
Magnetic resonance techniques, in particular phosphorus (31P) and deuterium (2H) magnetic resonance, in combination with selectively deuterated lipids, have yielded quantitative information on the ordering, motional anisotropy, and dynamics of membrane components. This information is essential for understanding the function of biological membranes.
The different structural elements of the lipid membrane include the polar part, constituting the interface to the aqueous compartment and consisting of the head group proper, the glycerol backbone, and the ester linkages. The molecular details of the membrane surface, including the electric surface charges, are relevant for membrane recognition by molecules such as enzymes dissolved in the extra- and intracellular space. The hydrophobic core region of membranes is formed by the fatty acyl chains of lipids. The order and dynamics of the hydrophobic core determine the permeability of the membrane to molecules such as drugs and may modulate the function of trans-membrane proteins. In addition to these elelments, we will also discuss the interaction of the lipid membrane with amphiphilic molecules, which penetrate into the hy-drophobic core region, and with intrinsic membrane proteins. The NMR results obtained by solid-state NMR will be compared with those obtained with neutron and X-ray diffraction and with recent molecular dynamics simulations of membranes.
