Form Follows Sequence

When the simulated temperature was raised high enough, their lattice model unfolded completely; when the temperature was lowered, the model refolded, writhing through almost a million different positions before settling into its native, low-energy structure. Even with a 48-mer model-roughly equivalent to a small protein-the possible initial conformations are astronomical, and each path to stability is potentially unique.

To see how different properties of the components may affect transition states and pathways, Rokhsar, Pande, and graduate student Nicholas Putnam designed three other small, 27-unit polymers with the same native-state conformation, based on three widely used types of lattice models.

In the simplest version, only mers that touched in the native state attracted each other-all others were energetically neutral. A more complex model had three kinds of mers in competition, with like types attracting one another more strongly than unlike types. The most complicated lattice model used mers with 20 discrete values derived from those of real amino-acid residues.

"In the two simpler cases, we found that folding pathways could pass through just two distinct core transition states," says Rokhsar. "The more complex model had only a single transition state. Both these behaviors are observed in the folding of some small natural protein structures."

Knowing more about the transitional structures that a folding protein must pass through sheds light on which positions in the chain of amino-acid residues are most critical for a flawless fold-those positions where mutations that substitute one amino acid for another are likely to have the greatest effect on a protein's shape, for better or worse.

Water, Water, Everywhere

Proteins don't exist as ideal Platonic forms; their real environment consists mostly of a warm solvent, namely water. By combining theoretical and computational approaches, such as lattice models, with data from experiments, physical chemist Teresa Head-Gordon of the Physical Biosciences Division and her colleagues have detailed water's essential role in driving protein folding and stabilization.