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A Place To Unlock The Hidden Life Of Molecules

This fall the University of Wisconsin-Madison will complete its new biochemistry building. The Department of Biochemistry has a storied history. Researchers there discovered vitamin A, the B vitamins, treatments for anemia and rickets, and both coumadin to prevent unwanted blood clots and Warfarin to kill rats.

Today biochemists increasingly rely on nuclear magnetic resonance (NMR) spectrometers to study the proteins that govern life. The machines can reveal how these molecules take form and if their three-dimensional shape changes as they carry out their functions.

The new building includes a laboratory large enough for the department”s NMR facility to bring all its machines under one roof. There is room to spare for future NMR machines, which may stand more than 20 feet tall, hold hundreds of miles of superconducting wire and carry a price tag of $6 million or more.

“We”re a national facility here to serve the scientific community,” says John Markley, the UW-Madison Steenbock Professor of Molecular Structure. Markley directs the NMR Facility at Madison (NMRFAM) with its five machines and staff of 10. “We analyze samples from researchers and train people who come here to do experiments with the machines.”

About 100 scientists from across the country have come to Madison to use the facility during the past three years. Recent projects range from how the AIDS virus constructs its outer capsule, to what makes a sweet substance sweet, to why some butter components are spreadable at refrigerator temperatures.

In this June”s issue of Nature Structural Biology, for example, Markley and UW-Madison coworkers described the structure of brazzein, a compound 2,000 times sweeter than sugar. Brazzein, isolated from a West African fruit, is one of a handful of compounds known to taste sugary to humans and other primates. The Wisconsin team included Markley”s graduate student Jane Caldwell, NMRFAM staff scientist Frits Abildgaard, and Goran Hellekant, a neurophysiologist in the Department of Animal Health and Biomedical Sciences, and his former student Ding Ming.

Markley believes knowing brazzein”s structure and how it binds to taste receptors will help scientists understand what gives the protein its flavor. His group has synthesized an artificial gene coding for the protein. The researchers are altering the gene so it produces slightly modified forms of brazzein. By studying the modified compounds, they hope to discover what parts of the structure are responsible for its sweetness.

Wes Sundquist, a biochemist with the University of Utah medical school, is spending three months at NMRFAM this summer. He”s one of many scientists documenting every change that happens inside the human immunodeficiency virus during an infection. Scientists recently developed drugs that inhibit the HIV”s protease enzyme, slowing the progress of AIDS. Sundquist studies a long protein that the protease must cut sequentially before the virus can infect another cell.

“We”re trying to get snapshots of what the protein looks like after it”s cut each time,” says Sundquist. He and co-workers have already used a method called X-ray crystallography to publish early “snapshots” of the protein”s transformation. Now Sundquist and NMRFAM assistant scientist Brian Volkman are using NMR to bring the protein”s final changes into focus.

NMR methods aren”t restricted to proteins. Fats and oils give many foods their distinctive flavor and texture. Experts at the Madison NMR facility helped food chemist Kerry Kaylegian at the University”s Center for Dairy Research apply NMR technology to dairy products.

Dairy researchers have now purchased their own small NMR machine. Kaylegian has used it in combination with other modern technology to develop a prototype of butter that spreads right out of the refrigerator; other researchers at the Department of Food Science use the NMR in studying ways to make ice cream even tastier.

Progress in genetics captures many science headlines these days. But even when researchers locate and sequence a gene, they can”t predict the shape of the protein that sequence encodes. Instead they depend on two approaches — X-ray crystallography and NMR spectroscopy — to solve the complex architecture of nature”s chemistry.

Markley says scientists need both techniques. Researchers today solve most protein structures with X-ray crystallography. It can be used on molecules of any size, but only those that form crystals. NMR technology can resolve the shape of molecules in solution, their natural state, where they can undergo what Markley calls their “full repertoire of kicking and breathing motions.” Until recently researchers could only apply NMR to small molecules.

Magnet size drives NMR technology. The machines operate on the same principle as the Magnetic Resonance Imaging (MRI) machines used in hospitals to diagnose diseases without surgery. Today”s NMR machines get the detailed resolution they need to analyze molecular structure by using powerful magnetic fields on small samples of purified compounds.

With the technology scientists can map the atoms in a molecule. NMR machines briefly create a strong magnetic field, to which some atomic nuclei respond by changing their alignment. Scientists can detect characteristic signals from this movement and use it to identify the atoms and their positions.

NMR machines have become larger over the years, which boosts both performance and cost, according to Markley, who began working with the machines in the 1960s and joined the UW-Madison in 1984. “Larger machines are useful because they make new types of experiments possible,” he says. Markley has published many papers on how to make NMR techniques more accurate and ways to use NMR to study how proteins change shape when they bind to other molecules.

Today”s largest machines are 750-megahertz to 800-megahertz class. Those machines have made NMR increasingly important in solving molecular architecture. NMR researchers now solve almost one-fourth of the 900 or so new protein structures completed each year.

“When NMRFAM got its 750 about three years ago, we were the third lab in the country to have one,” says Markley. Unfortunately, that NMR was too big to fit into the facility”s current building. Instead, NMRFAM set up the machine at a building about a half mile away from its four other NMRs. The 750 NMR will be the first machine put in place in the new lab, probably in September, according to Markley.

Manufacturers are now developing 1000-megahertz NMR models. Their larger magnets will mean even greater sensitivity. When the new machines come into use in a few years, scientists anticipate that they will be able to resolve the shape of molecules ten times larger than those that 1990-vintage machines could tackle.