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Supercomputer simulation of enzyme DNA interaction
Pittsburgh Supercomputing Center
Pittsburgh, PA

Year: 1993
Status: Award Recipient
Category: Science
Nominating Company: Cray Research, Inc.

Interaction between proteins and DNA is a fundamental biological process. Using supercomputing to simulate this process is an endeavor in basic research that benefits society by creating greater ability to control human disease and improving the quality of life.
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."

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 supercomputing system at
the Pittsburgh Supercomputing Center to 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."

Nature's Scalpels: Restriction Enzymes

For 15 years, Rosenberg and the scientists he works with at his
University of Pittsburgh laboratory have studied the DNA-recognition
mechanisms of a protein called Eco Rl endonuclease. Eco Rl is one among
a class of enzymes, called restriction enzymes, that protect the DNA in
bacterial cells by attacking DNA brought in by viruses and other foreign

"Eco Rl is one of the most frequently used in what's called recombinant
DNA technology," says Rosenberg, "or in the Jargon 'cloning.' These
enzymes recognize a particular sequence of bases of DNA and cut the DNA
at those sites, breaking it into well-defined pieces that can be put
back together in new combinations. Eco Rl is the prototype, the first
one of these enzymes to be understood and the first one used in this

The CRAY Biology Lab

Rosenberg and his graduate students, now Ph.Ds, John Grable and
Yongchang Kim used X-PLOR, an efficient program for refining the
structure of biological molecules (developed by Axel Brunger of Yale),
to help identify the mechanisms by which Eco Rl recognizes a particular
sequence of DNA. These computations resulted in clarification's to the
structural model of Eco Rl and how it binds to DNA. Their computations
showed that the protein wraps almost completely around the DNA, as if
embracing it with extended arms, and at the same time kinks the DNA at
the site where it binds.

Part of the structure resembles the structure of other enzymes that bind
to "nucleotides." Rosenberg believes that this portion of the structure,
called the nucleotide-binding fold, may be one of the keys to
understanding protein-DNA recognition. "This architecture is connected
very deeply to how proteins recognize nucleic acids. In an evolutionary
sense, it's one of the ancient patterns."

Large-Scale Molecular Dynamics

With recent physics Ph.D. Shankar Kumar and Peter Kollman of the
University of California at San Francisco, creator of the AMBER
molecular dynamics program, Rosenberg designed Y-MP simulations of the
kinked DNA to examine whether the kink was intrinsic to the DNA or was
caused by binding with Eco Rl.

"The computations gave us a very definite answer," says Rosenberg, "that
the kink results from binding with the protein, and this leads to a
whole series of ramifications about how the system works."

In other simulations with AMBER, Rosenberg and Kumar stretched the
limits of computational biology. Their simulations of DNA in solution
(with 1970 water molecules for 81 picoseconds) represent one of the most
extensive molecular dynamics computations on DNA molecules to date.