Gō -ing for the prediction of protein folding mechanisms

Protein folding has been a long-lived problem in biophysics. Much important progress has been made in the 90s by focusing on small single-domain proteins (1). In particular, (i) site-resolved measurement of the folding transition state ensemble, quantified as φ-values (2), made it possible to understand folding mechanisms relatively unambiguously, stimulating interaction between experimentalists and theoreticians; (ii) the energy-landscape theory (3) gave us a general framework based on statistical physics; and (iii) the finding of a significant correlation between folding rates and native structure topology (4), which suggested that the native topology is a key determinant of folding mechanisms, all lead us to believe that the underlying physics could be relatively simple. These three ingredients are linked together with an almost one-line free energy equation in three papers (5–7), which appeared in a recent issue of PNAS, as well as some previous work (8, 9). The surprise of the three papers is that apparently one can have both simplicity and fair predictability. Papers by Galzitskaya and Finkelstein (5), Alm and Baker (6), and Munoz and Eaton (7), which are independent but resemble each other greatly, report that even highly simplified theories based on energy-landscape ideas can predict trends in the folding rates for many fast folding proteins.