A simple theoretical model goes a long way in explaining complex behavior in protein folding

Understanding how natural proteins fold spontaneously onto their specific, biologically functional 3D structures is both a fascinating fundamental problem in modern biochemistry and a necessary step toward developing technologies for protein engineering and designing protein-based nanodevices. One of the limitations that scientists working in this area have encountered in the past, however, has been the difficulty in connecting analytical theory to experimental results. For a long time experimentalists could not use theory to interpret their results. Theoretical predictions, moreover, were not amenable to experimental testing. Such limitations have been progressively eliminated by the combination of key theoretical concepts, improved simulations, and new experiments and their detailed quantitative analysis with simple statistical mechanical models. The work of Inanami et al. in PNAS (1) provides a remarkable example of how powerful these simple theoretical models can be in explaining the complexities and nuances of protein folding reactions.

The first major step toward connecting theory and simulations to experiments was initiated by the development of ultrafast kinetic techniques, which led to the experimental determination of the relevant timescales of elementary processes in protein folding such as secondary structure formation and hydrophobic collapse, as well as the identification of several small proteins that fold rapidly (in microseconds) (2). It then became possible to obtain experimental estimates of the folding speed limit (3), a parameter that is essential for interpreting experiments in the context of energy landscape theory (equation 10 in ref. 4). Based on these estimates, the thermodynamic analysis of experimental protein-folding rates revealed that the free-energy barriers to protein folding are indeed entropic bottlenecks (5), as postulated by theory (4). Work on fast-folding proteins also led to the experimental identification of downhill folding (6), a bona fide prediction from energy landscape theory that has encountered tremendous resistance by some experimentalists within the protein-folding …

↵¹Email: vmunoz3{at}ucmerced.edu.