YouTube Facebook LinkedIn Google+ Twitter Xinginstagram rss  

By Karen Hopkin

June 12, 2002 | To understand why determining a protein's structure is so computationally intensive, imagine enumerating and sifting through the potential structures that might be adopted by a modestly sized protein only 100 amino acids in length. If each of those 100 residues could assume, say, one of five possible configurations, that protein could choose from 5100 or about 1070 possible conformations — a value that falls in the neighborhood of the number of atoms in the universe. Yet in a cell, this protein will typically fold spontaneously in less than a second.

But not all proteins can fold as quickly by themselves. Some receive assistance from specialized protein "chaperones" that keep folding polypeptide chains from getting tangled into useless clumps, perhaps by preventing them from heading down conformational blind alleys or by discouraging them from interacting inappropriately with other nearby proteins.

Other proteins use different tricks to help them fold and stay folded. A bacterial enzyme called alpha-lytic protease (alphaLP) comes with a built-in switch — part of the protein sequence itself — that triggers efficient folding. Studies by David Agard, a Howard Hughes Medical Institute investigator at the University of California at San Francisco, indicate that without this catalyst, alphaLP would take literally thousands of years to fold. Once the protein is properly folded, the trigger sequence is degraded, effectively locking alphaLP in its correct conformation. In the absence of the trigger, the protein takes more than a year to unfold again.

Allowing proteins to unfold, or fold incorrectly, can be disastrous for a cell or an organism. Cystic fibrosis, the most common genetic disorder among people of European descent, may be in large part a "folding disease."

The most common mutation in patients with CF removes just a single amino acid residue out of the 1,500 or so that make up the cystic fibrosis transmembrane regulator (CFTR) protein. This tiny deletion, however, wreaks havoc with the normal folding of CFTR, leaving the molecule an unraveled, misshapen mess. This failure to fold prevents CFTR from reaching its normal location and carrying out its job in the outer membrane of epithelial cells. Loss of CFTR in the lungs of people with CF renders them highly susceptible to the chronic Pseudomonas respiratory infections that eventually prove fatal. By finding a drug that would help mutant CFTR proteins to fold, scientists could cure the disease.


Back to Computational Biologists Join the Fold 

For reprints and/or copyright permission, please contact Angela Parsons, 781.972.5467.