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The chemistry of life's building blocks

While X-ray crystallography allows researchers to identify protein structures that form crystals, many proteins are difficult to grow into crystals.

For these “difficult” proteins, a different technique called nuclear magnetic resonance spectroscopy, or NMR, is commonly used to study their structure. To use NMR,though, the specific atoms in the proteins must first be “labeled ” or “tagged ” to make the identifiers visible.

The tagging process is necessary because all proteins, which are composed of amino acids, are made up of carbon and nitrogen atoms. Unfortunately, regular carbon and nitrogen atoms are invisible to the NMR. To get around this, Los Alamos scientists Ryszard Michalczyk, Jurgen Schmidt, Rudy Martinez, Clifford Unkefer and Pete Silks are using synthetic chemistry to imitate nature to recreate the building blocks of proteins—amino acids. As the scientists synthesize the amino acids, they change them slightly by replacing the regular carbon and nitrogen with special, stable isotopes of the elements that have one additional neutron. For instance, instead of regular carbon-12, they will insert in its place carbon-13. The NMR is able to “see ” these stable isotopes. The group also has developed similar chemistry for the building blocks of DNA and RNA nucleotides. The team studies protein and DNA molecules labeled with these stable isotopes using NMR methods.

One of the big challenges has been to find ways to streamline the methods of synthesizing new molecules so that it can be done using the smallest amounts possible of stable isotopes. This is important because the stable isotopes, such as carbon-13 or nitrogen-15, are very expensive.

In addition to researching the structure of proteins and DNA, the group also is working on developing synthetic, biomimetic (nature-imitating) compounds that could ultimately be used in types of “antisense” therapy. For instance, the group is studying the possibility of creating DNA analogs (molecules that mimic DNA structure). These analogs could bind to defective genes—those that are causing a particular disease—and provide a “marker” for disease detection.

The research being conducted now is a long way from medicinal or diagnostic applications, but it demonstrates some of the exciting possi- bilities that may lie ahead. The National Institutes of Health Stable Isotope Resource (more information can be found in “Stable Isotope Research Resource: Structural Biology Research Depends on Supply of Labeled Building Blocks”) has been critical to the success of Los Alamos' synthetic chemistry efforts, serving as one of the major funding sources for critical research and development work.

Also on the cutting edge of molecular synthesis is the research being done by Martinez. He is collaborating with Los Alamos computer scien- tists and theoretical physicists to create compounds that are used in quantum computing research—a whole new type of computing in which computations could be done in a tiny molecule, as opposed to today’s central processing unit. The speed of quantum computers one day might be marshalled to model the most complex systems we know—a living organism or perhaps even an ecosystem.



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