Shaping the future

“You need large quantities of proteins, but they need help in folding (organizing themselves into the proper shape) when produced in large quantities,” said Geoffrey Waldo of Los Alamos’ Bioscience Division, developer of the technique. “Our assay lets us evolve new versions of proteins that fold properly.”

The method involves fusing a green fluorescent protein, or GFP, with a target protein. The GFP fluoresces only in the presence of successful folding, showing which colonies of cells are the most valuable for propagating. The shape and function of the target protein does not have to be known to use the technique, says Waldo. In recent months, Los Alamos researchers have used the folding reporter assay and other techniques for the first time to complete a full set of experiments from initial engineering of a protein to a full analysis of its structure.

The technique is a key element for the work of an international consortium conducting research to analyze the structures of some 400 proteins of the bacterium that causes tuberculosis, the world ’s No.1 infectious disease, as declared by the World Health Organization to be a global health emergency. The Los Alamos-led collaboration, which involves approximately 40 institutions in move than 10 countries, received a five-year, $28.5 million grant last fall from the National Institutes of Health for the project. The TB research project also will use other innovative technologies developed at Los Alamos, according to project leader Tom Terwilliger of the Bioscience Division. One of them is SOLVE, a computer program that creates 3-D pictures of protein molecules faster than any other method. SOLVE, which produces electron-density maps based on X-ray diffraction data, is used at more than 300 universities and research institutions around the world. “By combining the technologies and experimental capabilities at Los Alamos with those of the entire TB structural genomics consortium, we are in a great position to make enormous progress in determining protein structures from TB,” Terwilliger said. Information developed during the project will be placed on the World Wide Web for use by other researchers and companies in efforts to develop more effective drugs and treatments for the disease.

Other strengths Los Alamos brings to studying the molecular frontier include powerful computational resources, large research facilities and a multidisciplinary research environment that includes experimental and theoretical capabilities. In addition to the understanding of basic biology and its consequences for human health, the Laboratory is applying its molecular research capabilities to national and international problems related to the environment and mitigating the grave threat of biological terrorism. Support for structural genomics research at Los Alamos comes from the Department of Energy’s Office of Biological and Environmental Research, the NIH and the internal Laboratory-Directed Research and Development program.