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Research
We construct experiments to explore a variety of topics in Biophysics and Soft Condensed Matter Physics. Throughout these fields, we encounter systems in which individually simple molecular components interact to give rise to complex, dynamic phenomena.
Some brief descriptions of topics of interest are presented below. See also the Papers section for publications related to some of these areas.
Membrane Biophysics
Cellular membranes are remarkable materials -- flexible, two-dimensional fluids at which mobile, nanometer-scale proteins play reactive and structural roles (see illustration). How do the material properties of membranes -- their rigidity, the mobility of lipids and proteins, their various phase transitions -- contribute to their function and their ability to spatially organize? How do the unusual structures and compositions of the membranes of various organisms contribute to their survival?
The biophysics of tuberculosis -- Mycobacterial membrane mimics
Tuberculosis infects about one-third of the human population and kills two million people every year. It is a remarkably robust organism, capable for example of surviving for months under conditions of extreme dehydration. Mycobacteria, which include the species that cause tuberculosis and leprosy, have membranes that are unusual in both their structure and their composition. To examine the role the membrane may play in conferring to the bacteria their remarkable physical properties, we have created artificial solid-supported membranes that mimic these mycobacterial envelopes (see schematic, below). These mimics allow new sorts of quantitative examinations of their physical properties by enabling control of membrane composition and quantitative assays of membrane behavior. We have recently discovered that a certain glycolipid present in all the mycobacteria has the ability to make membranes resistant to dehydration. Moreover, even as a minority component, this mycobacterial lipid protects membranes against desiccation. This is the first dehydration-resistant lipid ever discovered. For details, see our recent paper (Harland et al., 2008) .
Membrane fluidity and membrane rigidity
We are developing new methods to probe the basic mechanical properties of membranes: their two-dimensional fluidity and their bending rigidity. Our approaches are based on new optical techniques, involving interferometry to measure nanometer-scale membrane deformations, and microrheological tools to measure molecular mobility. Though 2D mobility is a fundamentally important attribute of biological membranes, its physical underpinnings are remarkably poorly understood.
Membrane-membrane interactions
Inspired by striking examples of spatial organization found at certain cell-cell junctions, we construct bilayer-bilayer junctions to unravel some of the relevant mechanics. For example, the picture above is from a fluorescence image of antibodies bound to a lipid membrane, after a second membrane comes into contact. Before the membrane-membrane junction is formed by the introduction of the second bilayer, the antibodies are uniformly distributed. When the junction forms, remarkable patterns emerge. The antibodies form "leopard spots" of high and low density (bright and dark in the image below). These protein patterns can be used to extract structural information about the proteins and the lipid bilayers themselves, as well as serving as a reminder that even simple situations can produce complex patterns.
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False-color fluorescence micrograph of antibodies at a membrane-membrane junction. The length-scale of the high- and low- density zones is related to the membrane rigidity and the protein mobility. Image width = 50 microns. |
Curvature and lipid phase transitions
Despite being fluid, cellular membranes are spatially non-uniform, an attribute of importance for the functioning of cell-signaling networks. Phase separation into chemically distinct domains (e.g. of "white" and "black" lipids in the sketch below) is believed to play a large role in driving membrane heterogeneity, but the means by which phase separation is controlled remain unclear. We have recently shown, using microfabricated materials to impart specific curvature profiles onto lipid membranes, that curvature is sufficient to control the spatial organization of phase-separated domains.
Macromolecular structure
We are developing new methods for examining the mechanical properties of proteins and other macromolecules. These include investigations of the role of glycosylation (the presence of sugar groups) on molecular rigidity, the mobility of protein domains about "hinge" regions, and the orientation of surface-anchored DNA.
Colloidal assemblies + optical traps
Can bio-membranes be used to create new, non-biological materials? We're interesting in using membrane-functionalization of microparticles (see illustration) as a means of controlling interparticle interactions and generating complex self-organized assemblies.
To reach these aims, we have invented new types of optical traps (see papers, Tietjen et al., 2008) that facilitate measurements of colloidal interactions and are developing additional approaches that will allow these composite particles to self-assemble into crystalline lattices.
Other Soft Materials
We are also interested other types of soft condensed matter, such as polymer gels, colloidal dispersions, and emulsions -- especially in contexts in which their structural properties can influence and be influenced by various bio-molecules.
Advanced Microscopy Techniques
To explore the above-mentioned topics, we use and also develop a variety of advanced optical microscopy techniques. These include methods based on optical interference that provide nanometer-scale probes of system structure. (See papers, Groves et al., 2008, for a recent review.)