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The Double Helix

The discovery of the double helix structure of DNA, worked out in its rudiments by Francis Crick and James Watson in 1952, is without question one of the scientific triumphs of this century. DNA is the basic repository of genetic information, an amazingly intricate molecular code governing the biological processes we call "life." Yet, as it tends to go when we learn about the world around and within us, the more we know, the more we don't know.

Nearly everything that happens biologically from DNA happens because many different proteins somehow have the ability to isolate their activity at specific sites on the long helical strands that comprise DNA molecules. John Rosenberg uses the CRAY Y-MP to help understand these complex processes, usually called protein-DNA recognition.

"There are large classes of proteins," says Rosenberg, "that recognize specific sequences of DNA, and they do very important things -- ranging from controlling which genes express when and how, to rearranging the structure of DNA itself. These are basic biological processes that we want to understand partly for their own sake, but also for two practical reasons: first, many disease processes may be related to aberrations in these events and, second, restriction enzymes are vital tools of the biotechnology industry."

Over more than 15 years, Rosenberg and his colleagues have carried on a sustained research effort aimed at understanding how protein-DNA recognition works in the case of a particular protein, Eco RI endonuclease. Using computational resources at the Pittsburgh Supercomputing Center, they have built a detailed model of the structure of Eco RI. Further computations also brought fundamental new understanding showing that a kink in DNA's structure is not inherent to DNA, as had been thought, but instead results from binding with Eco RI.

For this work, Rosenberg received the 1991 Forefronts of Computational Science award. The 1993 Computerworld Smithsonian award for science and the 1994 Discover magazine science and technology awards also recognized Rosenberg's research for using supercomputing to advance the quality of human life.

This ribbon model from Rosenberg's calculations shows front, side, and top views of the restriction enzyme Eco RI endonuclease wrapping around DNA (blue). The enzyme is composed of two symmetrical subunits (red and yellow) that correspond to the twofold symmetry of DNA's double helix. Each subunit kinks one ot the DNA backbones (which can be seen in the side view) and like scissors snips the DNA at the kink. Because of its ability to cut DNA at this precise location, Eco RI has become one of the biotechnology industry's most important tools for cloning DNA.

ANIMATION: Eco R1 Endonuclease (1,590KB mpeg)
This video animation, which zooms in on the structure of Eco RI endonuclease (blue and red) and the segment of DNA (green) it binds to, was produced at PSC by David Deerfield, Joe Lappa, Greg Foss and Marcela Madrid from computations by John Rosenberg and his colleagues.

Researcher: John M. Rosenberg, University of Pittsburgh.
Hardware: CRAY Y-MP
Software: X-PLOR, AMBER
Keywords: DNA, restriction enzyme, Eco RI endonuclease, genetic engineering, moleclular dynamics, biophysics, biotechnology, double helix, protein-DNA recognition, nucleic acids, cloning, DNA analysis, nucleotide-binding fold, molecular strain, nucleotide chain, protein structure rerefinement.

Related Material on the Web:
Projects in Scientific Computing, PSC's annual research report.

References, Acknowledgements & Credits