Latest folding game results: Protein A barely frustrates computationalists

The dark mystery of protein folding has been greatly illuminated by the last decade's work. This enlightenment has come from the simultaneous flowering of new theoretical approaches (1–3), powerful computational studies (4, 5), and a fresh wave of experiments using protein engineering (6) and ultrafast kinetics (7, 8). How a disordered chain molecule finds its organized, folded state is no longer a paradox, but a scientific problem requiring a close comparison of theories, computation and experiments. A beautiful experimental study of the mechanism of folding of the B domain of streptococcal protein A appears in this issue of PNAS (9). This study joins such landmarks as the elucidation of the folding mechanism of CI2 and barnase by the same group (10). So what's the news? The excitement comes because this protein has been the poster child of computational folders. It is attractive to computationalists because of its small size, 60 residues, at the extreme limit exhibiting cooperative protein-like thermodynamics. The protein also folds fast, so computer studies have the best chance of success. Numerous simulations were carried out (11–23) without extensive laboratory kinetic studies at the residue level to influence the work. It is thus interesting to see how well the computationalists have been able to predict the folding mechanism without much biasing data.

Sato et al. (9) liken the comparison of simulations with their kinetic experiment to the biennial exercise Critical Assessment of Structure Prediction (CASP) (24). They, like most participants in CASP, refer to it as a competition, although the organizers decry that appellation. As the leader of a participating group, I can testify to CASP's painfulness, but, despite its undignified similarity to a sporting event, good science comes from CASP. Likewise, the present results do indeed provoke serious thought.

When compared …