"Learn to love the questions themselves,
like locked rooms,
like tappings behind dark glass."
--Rainer Maria Rilke

Proteins and Progress

When Watson and Crick worked out the three-dimensional structure of DNA in 1953, their achievement opened doors onto a realm of scientific problems that until then had been glimpsed as if looking through a keyhole. Their work helped to spawn the science of molecular biology, and its primary task since then has been to determine the three-dimensional structure of thousands of very large, complex molecules, predominantly proteins, that govern the intricate web of biochemical reactions we call life.

Progress has been difficult, often involving years of work to solve the puzzles posed by a single protein. In the late 50s, Max Perutz and John Kendrew at Cambridge won a Nobel prize for working out the structure of hemoglobin and its close cousin myoglobin -- the first proteins solved. Since then researchers have solved hundreds more, slowly and steadily building an invaluable body of knowledge.

The ultimate goal of this work is to attack disease at its molecular roots. When relationships between molecular structure and biological function are understood well enough, it could be possible, for instance, to design proteins to lower blood pressure or halt the growth of malignant cells. These are rich possibilities for improving the quality of human life, yet the primary task today remains much as it was in the 1950s -- to determine the three-dimensional structure of proteins.

Oleg Jardetzky, director of the Stanford Magnetic Resonance Laboratory, and his colleagues have pioneered the development of Pittsburgh Supercomputing Center during the past year overcame the final stumbling blocks, and the results show that flexibility of the protein is key to its interaction with DNA. "It's like getting a handshake," says Jardetzky. "You can't do it with rigid hands."


Trp Repressor and DNA
"Shaking Hands"

This graphic represents the structure of trp-repressor bound to DNA as determined from NMR data obtained by Oleg Jardetzky and colleagues at Stanford Magnetic Resonance Laboratory. Structurally, trp-repressor is a symmetric dimer, a molecule formed of two identical subunits (light blue and pink) intertwined with each other. The red atoms represent the two tryptophan ligands, molecules that bind with the represssor before it binds with DNA (light green).

Calculations at the Pittsburgh Supercomputing Center (conducted by Daqing Zhao) showed that the tryptophan ligands stabilize the otherwise more flexible DNA-binding region of the protein and hold it at an optimal configuration for binding with DNA.

The repressor regions directly above and below the tryptophan are the protein's "reading heads." They make direct contact with the DNA, wedging into DNA's "major groove" -- the opening that forms between DNA's two helical backbones. The DNA, in turn, bends at each end to wrap around the protein.

Researchers: Oleg Jardetzky & Daqing Zhao, Stanford University.
Hardware: CRAY C90
Software: PROTEAN, X-PLOR, CHARMM
Keywords: DNA, trp-repressor, simulated annealing, molecular dynamics, nuclear magnetic resonance, NMR, protein structure, biosynthesis, x-ray crystallography, tryptophan, amino acid.

Related Material on the Web:
More information on Stanford Magnetic Resonance Laboratory, Projects in Scientific Computing, Daqing Zhao's homepage. PSC's annual research report.

References, Acknowledgements & Credits