One of ORNL's newest user facilities is already among the most popular.
When ORNL's Center for Structural Molecular Biology (CSMB) opened its doors in 2007, Chemical Sciences Division Director Phil Britt was a little surprised at the number of users attracted to the facility that today is helping to make ORNL a leader in neutron-based studies of bio-molecular structure. "We built the center hoping demand would be high," Britt said. "As it turns out, not only are users lining up to conduct research, but the line goes out the door and around the building."
Center staff scientist Volker Urban recalls that "once the center started showing promising results, we quickly generated a backlog of users, followed by a growing number of invitations to participate in grant proposals." The center teamed with Washington University in St. Louis to win a highly competitive Energy Frontier Research Center proposal to study the biological mechanisms plants use to convert sunlight to energy, research that could lead to the development of much more efficient solar cells. In another energy initiative, researchers at the center are working with the Department of Energy's Genomes to Life Biofuels program, using unique characterization and analysis capabilities to convert biomass to bio-fuels more efficiently.
The level of enthusiasm on the part of both users and research sponsors is understandable given the center's ability to reveal the three-dimensional structures and assemblies of biological molecules, such as proteins, lipids and DNA. Understanding the molecular structure and interactions of these molecules assists researchers in determining how the molecules are formed and how they influence the function of living cells.
"The approach we have taken provides a complete ‘structure solution toolkit' for the biology community," explains center director Dean Myles. "We make available a pipeline in which users can start from a single gene and synthesize molecules at the laboratory bench, measure and characterize these molecules using neutron beams and then analyze these data using advanced computational techniques to determine 3-D models of the molecular structures. The approach represents a one-stop shop for structure solution." The center's users have access to a diverse range of research interests. To aid researchers in exploring questions related to energy, medicine and a range of other fields, the facility applies three primary research tools:
BioSANS – The cornerstone of the center's research capabilities is a small-angle neutron scattering instrument called BioSANS. Located at ORNL's High Flux Isotope Reactor, the BioSANS instrument uses a neutron beam from the reactor to probe the structure of functional biological systems at the nanoscale. This technology enables researchers to determine the structures of both individual biological molecules and molecules interacting and assembling in the functional complexes of the cell.
While similar instruments exist at other facilities, BioSANS is among only a few in the world specifically tailored to tease out the nuances of biomolecular structure. Researchers achieve this specialized capability by making several accommodations for the peculiarities of biomolecules. First, BioSANS uses less energetic, "cold," neutrons, which have wavelengths tuned to help "see" the soft material contained in most biological samples. Second, the instrument itself is designed to be extremely sensitive, minimizing sources of background noise that might interfere with measurements of small, dilute solutions of biological material. Finally, the center's biodeuteration facility (described in more detail below) enables researchers to enhance the samples further, making it possible to label individual components with deuterium and increase their "visibility" on the BioSANS.
"This combination of capabilities is unique in the United States," Britt says. "There are several similar facilities outside the U.S., but none is dedicated to biology. Moreover, at 85MW, ORNL's High Flux Isotope Reactor is the world's most powerful steady state neutron source." The intense neutron stream means that measurements taken on the BioSANS instrument can generate higher resolution data from smaller samples in less time than can be achieved at any other facility in America.
Bio-deuteration laboratory – The technique of bio-deuteration enables biological molecules to be labeled selectively by substituting deuterium, a specialized form of hydrogen, for normal hydrogen atoms. Because deuterium scatters more neutrons than hydrogen, deuterium-labeled molecules can be examined with unusual fidelity by the BioSANS. The technique is particularly effective in highlighting specific parts of target molecules, such as reaction centers, and in distinguishing the presence of labeled molecules incorporated in larger biological complexes or assemblies.
"All samples do not require this technique," Britt adds. "Individual molecules and biological complexes can often be analyzed directly on the BioSANS, but when users address more complicated questions, biodeuteration adds another dimension."
Despite obvious advantages, the technique of bio-deuteration is not without challenges. When a sample needs to be labeled with deuterium, researchers perform the work in a solution of deuterated or "heavy" water. For some biological samples, the chemistry and physics of "heavy" water can be a problem. "Most enzymes and microorganisms do not perform well in deuterated water," Britt observes. Fortunately, center staff members have a repertoire of skills and systems available to address such problems. Myles believes these techniques have advanced to the level where researchers can target and label even individual amino-acid groups in selected proteins or leave only a few hydrogen atoms in place to highlight the functional sites.
Computational modeling – To support the user program, the center has developed a suite of advanced computational tools for creating 3-D models of complex biomolecules from data collected using BioSANS. These detailed structural models are critical to providing scientists with an understanding of how biomolecules function in living systems.
Urban cautions that, "the results we get from these studies are only as good as the software we have to analyze the data." He views computational modeling as another area in which the center's integrated approach comes into play through the development of computational tools to help interpret and understand the data. The tools enable structural information from other experimental techniques to be combined with the information gathered from the BioSANS, making it possible to develop even more complex and sophisticated 3-D models. "The process is like building a jigsaw," Myles says. "If we already know something about the individual pieces of a biological structure, these tools help us use the BioSANS data to build those pieces into more detailed models to complete the puzzle."
A continuing commitment
The user community's enthusiastic response over the first three years of operation make it clear that the center is not only making neutron scattering available to users in the broader biological community but is also attracting users who even five years ago would never have considered using neutron scattering as a research tool. Today, the center supports users from a range of scientific disciplines, including biophysics, chemistry, biology and computational sciences. As a result, many of the studies conducted address questions that have not, or in some instances, could not, have been answered by other techniques.
The center's success can be attributed to a unique approach and combination of analytical tools, the expertise of a world-class staff, the successful integration with other superlative research facilities such as the High Flux Isotope Reactor and the Spallation Neutron Source, and an ongoing commitment to provide users with the tools and support necessary for breakthrough research. Phil Britt sees in the collection of assets a promising future in which one of ORNL's newest user facilities continues to strengthen its reputation as one of the world's leading laboratories for neutron-based studies of biomolecular structure and function.
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