Form Follows Sequence

One important measure of amino acids is their varying degrees of hydrophobicity, or "fear of water." Oil is hydrophobic-that's why oil drops remain separate in water-while hydrophilic ("water-loving") substances readily dissolve in it. Many proteins have a hydrophobic core and a hydrophilic surface.

By measuring the intensities of x-rays or neutrons scattered by water molecules alone - and then by leucine molecules dissolved in water-Head-Gordon and her colleagues were able to analyze the structure of water near the leucine. They conjectured that these water structures, much more highly ordered than water in bulk, give rise to forces that differ among different kinds of amino acids and thus influence folding pathways.

When Head-Gordon and her colleagues applied what they had learned from scattering experiments to lattice models of polymers, they found that by including accurate solvation forces they could go a long way toward making the models more realistic mimics of actual proteins. Some models were swiftly eliminated, and the performance of others was improved to exhibit faster folding and more cooperative folding transitions. In addition to a basic understanding of the folding of all proteins, such studies may lead to specific insight into classic sequences such as the "leucine zipper" that joins secondary protein structures into dimers through hydrophobic attraction-a sequence that, when mutated, may play a prominent role in activating cancer-causing genes.

SCOPing Out Folds

Simple theoretical models bolstered by experimental data are one approach to faster protein-structure prediction. Another way to use computers to translate dna sequences into protein structures is to work directly from a growing library of known folds.

Describing her method of predicting the folds of unknown proteins, Dubchak explains that "traditional methods compare unknown gene sequences to known protein sequences or structures residue by residue, searching for correspondences. But what happens when no similar sequence exists? I decided to tackle the problem differently, from a taxonometric perspective."

Dubchak assessed the physical properties of each of the 20 amino acids found in proteins-such characteristics as hydrophobicity, polarity, van der Waals radius (size), and the like-and reduced these to a number of vectors representing the residue's cooperative influence on a fold.

Taken together, the vectors of an unknown sequence do not specify an exact shape so much as they suggest one that may or may not resemble a fold already included in the Structural Classification of Proteins (scop), a library of experimentally observed folds developed by the Medical Research Council's Laboratory of Molecular Biology in Cambridge, England.