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This illustration shows a designed protein
transformed from an unfolded into a folded form.
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"What drives this polypeptide chain to fold
up?" asked Harold Scheraga, professor emeritus of chemistry and
chemical biology at Cornell and a co-author of a paper published in
the Aug. 29 issue of the Proceedings of the National Academy of
Sciences (and available online). "That has been the subject of my
investigations for some time, and the cited experimental verification
of the theory provides a sound basis for further computational work to
identify the specific steps in the folding pathway.
"Protein folding is a frontier problem in protein
chemistry," said Scheraga, noting that an ability to predict how and
where proteins fold could lead to understanding such protein
misfolding diseases as Alzheimer's and cystic fibrosis, designing
drugs that act on proteins and even creating designer proteins with
new functions.
The theory is based on two methods to show that
initial folding sites occur among nonpolar groups in a polypeptide
chain. Lead author H. Jane Dyson and Peter Wright, both professors of
molecular biology at the Scripps Research Institute, used an
experimental nuclear magnetic resonance procedure to validate the
predicted results of the two theoretical methods.
The first method used supercomputers to calculate
the energy required to convert a polypeptide chain into a collapsed
hydrophobic pocket. The folds occur in several places that require the
least possible energy to maintain. By finding these places where the
nonpolar groups exist, the researchers better understand where folding
occurs along a linear polypeptide chain.
The second method involved mapping a folded protein
by tracing the folding steps required to arrive at the protein's
native structure. This method mapped three stages of folding. First,
the short-range contacts between amino acids that are very close to
each other were mapped, revealing the initial nonpolar (hydrophobic)
folds. The next two stages show folds that occur between points that
are farther from each other along the polypeptide chain. These
secondary folds may attach two or three hydrophobic pockets.
These two methods were used together in this study
to pinpoint where on a polypeptide chain the nonpolar segments occur
and where initial folding takes place and then propagates to the final
folded form |
