The Protein-Folding Problem

A droopy, strung-out chain of amino acids that isn't much good for anything -- that's what rolls off the assembly line of the molecular factory inside a cell when a protein is created. All the pieces are there, and they're in the right sequence. Yet the new protein is unfit for duty. It isn't in shape.

To do its job, whatever it may be among the thousands of life-sustaining jobs proteins do, this dangly chain forged from hundreds of amino acids must fold into just the right three-dimensional configuration. It happens within seconds, a long time in protein biochemistry, and the result is a complex bundle of twists and turns with clefts and notches precisely sculpted to allow the protein to attach and release other molecules. Function follows from form, and when the form is right, the protein goes to work.

For biomedical scientists, this phenomenon poses the kind of mystery science thrives on. How is it that a particular sequence of amino acids uniquely determines the right shape, out of almost unlimited possibilities, so that the protein can perform its predestined biological role? It's called the protein-folding problem, and solving it is no mere intellectual exercise. In theory, knowing the biological laws that govern protein folding could make it possible to create new proteins made to order to cure diseases and abate maladies from indigestion to arthritis.

"The relationship between protein sequence and three-dimensional structure is one of the primary unsolved problems in biology today," says Charles Brooks, who is attacking this Grand Challenge problem in several related projects at the Pittsburgh Supercomputing Center. Brooks is a leader in the development of a computational method called molecular dynamics (MD). He helped develop the CHARMM package of MD software, used by a number of researchers working in protein and DNA structure analysis, and he has been applying MD in protein research at the Pittsburgh Supercomputing Center since it opened its doors in 1986.

In a series of very large-scale simulations on the CRAY C90, Brooks has explored protein folding in apomyoglobin, a partially unfolded form of myoglobin, a protein that carries oxygen in muscle tissue. His results have begun to identify intermediate folding stages along the folding "pathway" of this protein. In a related project, Brooks has collaborated with PSC biomedical scientist Bill Young, to develop a version of CHARMM that distributes MD computations between the CRAY T3D and C90, significantly boosting performance for MD simulations.

Researchers: Charles L. Brooks III, Carnegie Mellon University; William S. Young, Pittsburgh Supercomputing Center
Hardware: CRAY-C90, CRAY T3D
Software: CHARMM
Keywords: protein, enzymes, antibodies, oxygen, protein-folding, amino acid, sequence, three-dimensional structure, molecular dynamics (MD), DNA structure, apomyoglobin, myoglobin, nuclear magnetic resonance (NMR), CHARMM.

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

References, Acknowledgements & Credits