John T. Elliott, Curtis W. Meuse, Vitalii I. Silin, Susan T. Krueger, John T. Woodward IV, T Petralli-Mallow, Anne L. Plant
Biological membranes are complex and dynamic structures. The biological functions associated with membranes involve a number of different molecular species, and theories of how the molecular species are organized are still evolving. The fluid mosaic model of freely diffusing proteins and lipids in a two-dimensional fluid  has been refined to account for the presence of functional domains [2-4]. The composition, dynamics, source, and even existence of discrete segregated features, such as membrane rafts, are currently sources of significant controversy [5,6]. As a result of ambiguities in the complex nature of biomembranes, better physical and theoretical models are constantly under development. Both lipid and protein components of membranes are responsible for membrane function as well as structure. In addition, membrane protein function can be influenced by the lipid matrix that surrounds it. Attempts to understand integral membrane protein structure at the atomic level by crystallization and diffraction remains a critical challenge. Only a few membrane protein structures have been determined by X-ray diffraction [7-9]. It is assumed that the protein s crystal structure is likely to be the same as that of the active protein in its native membrane environment; in fact, the function of bacteriorhodopsin in crystals has been demonstrated directly . Nevertheless, part of the challenge associated with membrane protein structures is that their native structure and function can be highly dependent on an appropriate lipid environment. Two-dimensional protein crystallization provides some promise of a general way of crystallizaing membrane proteins in the presence of lipid or detergent [II]. In general, the lipid environment is highly dynamic, and moving molecules are not good subjects for X-ray diffraction. Understanding how membrane protein structural changes are responsible for functions such as transport and signal transduction is a critical issue. Active biological membranes are dynamic on a time scale of minutes and hours at the cellular level (e.g., membrane trafficking), and on a scale of milliseconds and nanoseconds on the intermolecular and intramolecular levels. The function of membrane proteins during transport of molecules across the lipid barrier, or during intracellular kinase activation resulting form an extracellular ligand binding to a receptor, likely occurs via protein conformational changes. In addition to such intramolecular dynamics, protein and lipid components diffuse laterally in the plane of the membrane, and different approaches to study diffusion can provide information on appropriately different time scales [12,13]. Furthermore, lipid components can diffuse between the membrane and the surrounding aqueous milieu, by a process that is well explained by thermodynamic considerations . infrared, neutron reflectivity, atomic force microscopy, sum frequency generation, impedance and electrochemical studies performed at NIST are presented.