In a multicellular organism, such as a human, cells must communicate with one another to coordinate their activities across the entire organism. Cells send messages to each other through signaling compounds that attach themselves in lock-and-key fashion to protein receptors present both on cell surfaces and inside cells. These signaling compounds include proteins, hormones, peptides, amino acids, and even dissolved gases.
An example of a signaling compound is the hormone estrogen, which swims around in circulating blood and interacts with its receptors located on the surfaces of cells within the endocrine system. Some small signaling compounds can pass through the cell membrane to interact with a receptor inside the cell, while others remain tightly bound to the surface of one cell and interact with receptors bound to the surface of a neighboring cell. Characterizing the details of these and other types of interactions of biomolecular complexes is the chief goal of a new DOE user facility at ORNL, the Center for Structural and Molecular Biology (CSMB). Michelle Buchanan, associate director of ORNL's Life Sciences Division (LSD), also serves as director of the CSMB. The CSMB includes scientists from LSD and from ORNL's Chemical and Analytical Sciences (CASD) and Solid State divisions, as well as from Los Alamos National Laboratory (LANL).
Artist’s conception of the cold neutron source–hydrogen moderator vessel, which is being built in 2000 and will be installed in 2001 in ORNL's High Flux Isotope Reactor. Neutrons from the reactor are slowed down by frequent collisions with the moderator’s hydrogen atoms. Because the collisions heat up the hydrogen, it must be cooled down by a helium refrigerator to remain an effective neutron moderator. The moderator vessel cutaway (above) shows the temperature of representative hydrogen flow streams.
"The new center is based on our traditional strengths in neutron science, mass spectrometry, and computational sciences," Buchanan says. "Our mass spectrometry and computational sciences capabilities are now open to outside researchers."
DOE's Office of Biological and Environmental Research supports the CSBM and is providing nearly $6 million to build a biological small-angle neutron scattering (Bio-SANS) instrument, which should be functioning by June 2002. Bio-SANS will be added to the guide hall of the new cold neutron source now being constructed at ORNL's High Flux Isotope Reactor (HFIR).
"The biological SANS instrument will be designed to have both high flux and low background, which is critical to the analysis of biological materials," Buchanan says. "The upgrade of the HFIR offers a unique opportunity to provide the biological community with a SANS facility that rivals the best capabilities in the world.
"X-rays give excellent high-resolution analysis of the structure of proteins in crystals," she says. "But some very important proteins cannot be crystallized. Also, scientists use nuclear magnetic resonance (NMR) and SANS to study these proteins in their natural form, in solution. Results from the Bio-SANS will not only complement data obtained from X-ray crystallography and NMR but also will provide unique information on the interactions of biomolecules in complexes involved in the cell-signaling processes."
CASD's Organic and Biological Mass Spectrometry Group has added several new mass spectrometers to supplement its current capabilities, including a high-performance Fourier transform ion cyclotron resonance (FTICR) instrument.
"The new FTICR is equipped with an electrospray ionization source, which will allow us to study large proteins and protein complexes," says Buchanan. "The instrument was delivered with a 7-Tesla superconducting magnet. It will be upgraded this summer with a 9.4-Tesla magnet, which will increase the performance of the instrument with respect to both mass resolution and dynamic range. We are very excited about having this instrument for biological studies."
LSD's Computational Protein Structure Group, which predicts protein folding and threading using sophisticated computer models, will assist with interpreting data on biomolecules obtained by researchers using SANS. This group will work closely with researchers at LANL to provide users with user-friendly software for the interpretation of data.
Buchanan sees a bright future ahead for the new CSMB. "We are just beginning to get the word out about the CSMB and have already had researchers from the University of Tennessee come to use the mass spectrometry resource."
Communication between scientific facilities and users may be just as important as it is between cells in multicellular organisms.
