Proteins are born resembling strings of beads. Then, as shown in the computer simulation at the left, they fold in an instant into intricate patterns that make them become brain, blood, biceps, and bone.

But sometimes something goes awry in the folding process. One result is disabling diseases like Alzheimer's and "mad cow" syndrome. They also cause respiration and locomotion failures because protein functions cannot be fully carried out. Yet, until now, biophysicists could only guess at what happened.

The problem was that even supercomputers were not up to the enormous computational task of describing the interactions between more than one protein molecule. In fact, no one had devised a computer algorithm that would model the interaction between just two protein molecules until Jonathan King of Massachusetts Institute of Technology recently teamed up with researcher Sorin Istrail of Sandia National Laboratories' computational biology project to do so.

"What Sorin has done is to say, 'If bumping is important, I will have a pair of strings move in space and bump into each other.' He quickly discovered properties of folding that were absent in previous simulations," says King, who pioneered "wet" laboratory experiments to uncover protein-misfolding mechanisms. A paper describing the work will be published this spring in the Journal of Computational Biology.

Using the model, developed by Istrail and MIT graduate student Russell Schwartz, the researchers tracked two highly simplified proteins interacting on a grid during millions of computerized trials. They found it was the apparently random positioning of water-loving (hydrophilic) molecules in a protein that prevents water-hating molecules (hydrophobic,which possess the dominant folding force), from binding with other proteins.

In Alzheimer's and other protein-based diseases, an amino acid from one protein links to an amino acid on a second protein, rather than waiting to link to one on its own chain. This protein "adultery," which occurs as each protein passes through a series of intermediate folding steps, results in proteins stuck to each other in inert masses.

The researchers found that, in an aqueous solution, amino acids usually hook up with others in their own string because of the randomness with which water-hating amino acid molecules are interspersed among water-loving ones on the same protein. The water-hating molecules are prevented from combining with their counterparts on other strings by the action of water-loving molecules, which form little pockets of protection around neighboring water-hating molecules. These pockets require another protein to have exactly the right shape to inject a corresponding amino acid into the tiny coastal boundaries created by the protectors. Which rarely happens.

"Our Monte Carlo [statistical] simulations unveil how the kinetic competition between folding and aggregation is resolved by the 'good' sequences' built-in protection against aggregation, due to their hydrophobic-hydrophilic pattern," says Istrail. "This allows them to escape misfolding traps and move towards the hypothesized 'fast track' folding that takes place for real proteins".

The results will help laboratory scientists understand the mechanisms by which incomplete folds occur, in order to prevent them. "This is a step toward successful protein engineering," says Istrail. "It provides our first clue in how to design sequences of laboratory proteins that can survive the essential but complicated folding process."