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
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.
The Department of Energy's Office of Science is the single largest supporter of basic research in the physical sciences in the United States and is working to address some of the most pressing challenges of our time.