SCIENCE NEWS ONLINE
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Volume 155, Number 10 (March 6, 1999)

Simulations nab protein-folding mistakesReferences

By I. Peterson

The human body manufactures thousands of different proteins, which act as enzymes, structural elements, or carriers. Each protein starts out as a long strand that must fold itself into the proper shape to perform its specific function.

To gain insights into the folding process, researchers have developed mathematical models that attempt to capture how a single strand rapidly collapses into its correct configuration (SN: 5/9/98, p. 296). New computer simulations now reveal how one protein strand can interfere with the folding of another.

"This is a step toward successful protein engineering," says computer scientist Sorin Istrail of the Sandia National Laboratories in Albuquerque. "It provides our first clue in how to design sequences of laboratory proteins that can survive the essential but complicated folding process."

The results could also help laboratory scientists understand the mechanisms underlying protein-folding mistakes, which are implicated in Alzheimer's disease (SN: 7/4/98, p. 4) and other maladies.

Proteins Istrail and his collaborators, biologist Jonathan A. King and computer scientist Russell Schwartz of the Massachusetts Institute of Technology, report their findings in an upcoming Journal of Computational Biology.

Each protein is a string of amino acids spelling out a characteristic sequence. Scientists divide the 20 distinct amino acids into two groups according to whether they attract or repel water molecules, the main constituent of cells. Those interactions drive protein folding, creating globular structures in which water-repelling amino acids end up on the inside and water-attracting ones on the outside.

A simple model portrays a protein as a stiff but jointed structure, made of two types of beads, that can snap into a few positions at each joint. Because of the huge number of different folding possibilities for even a short strand, however, simulating the process on a computer has proved difficult.

Moreover, protein strands in cells have many jostling neighbors, King notes. Two partially folded protein molecules may end up sticking together.

To capture that additional complication, Istrail and his coworkers started with a well-studied, jointed-structure model originally developed by Ken Dill of the University of California, San Francisco. Taking advantage of Sandia's powerful computers (SN: 7/5/97, p. 5), the researchers examined what happens when strands move about and bump into each other.

Although the specific amino acid sequence determines the protein's function, the location of water-attracting components appears to be random. By tracking two highly simplified protein chains interacting on a grid, Istrail and his coworkers showed that this irregular arrangement plays an important role in preventing water-repelling units from binding to those of another strand.

A protein with an ordered distribution of water-attracting units tends to aggregate with other proteins to form an inert lump, Istrail says. Random positioning appears necessary to keep different strands apart, allowing the formation of the correct folds.

References:

Istrail, S., J. King, and R. Schwartz. In press. Lattice simulations of aggregation funnels for protein folding. Journal of Computational Biology. Available at http://www.cs.sandia.gov/~scistra/.

Further Readings:

Hayes, B. 1998. Prototeins. American Scientist 86(May-June):216.

Peterson, I. 1997. Computing nuclear crash and burn scenarios. Science News 152(July 5):5.

Richards, F.M. 1991. The protein folding problem. Scientific American (January):54.

Seppa, N. 1998. Amyloid can trigger brain damage. Science News 154(July 4):4.

Wu, C. 1998. Hot-blooded proteins. Science News 153(May 9):296.

Sources:

Ken Dill
University of California
Department of Pharmaceutical Chemistry
San Francisco, CA 94305

Sorin Istrail
Sandia National Laboratories
Mail Stop 1110, Department 9222
Albuquerque, NM 87185-1110
Web site: http://www.cs.sandia.gov/~scistra/

Jonathan A. King
Massachusetts Institute of Technology
Department of Biology
Cambridge, MA 02139
Web site: http://web.mit.edu/biology/www/Ar/king.html


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