The nature of the protein folding transition state
By: Patrícia Faisca
From: CFTC
At: Complexo Interdisciplinar, Anfiteatro
[2009-02-18]
The transition state (TS) is perhaps the most important milestone in two-state folding kinetics since it represents its rate-limiting step. Likewise, it is important to unravel its structural features. Due to its fleeting nature, however, the commonly available biophysical tools have revealed inappropriate to probe the TS structure. Thus, experimental studies of the TS have remained predominantly rooted in the use the phi-value analysis, which provides an indirect view of the TS structure. Moreover, the PVA has been the target of a recent series of criticisms that, if proven correct, will weaken our current view of the TS. Simulations of protein folding can play a significant role in investigating the relevance of such criticisms and evaluate its impact in our current understanding of the protein folding TS and mechanism. Indeed, a clear advantage of molecular simulations over experiments with real proteins is the ability to isolate every single conformation along the folding pathway and directly inspect its structure. Furthermore, the use of the so-called folding probability reaction coordinate (which is equivalent to the transmission coefficient in the parlance of rate theory) allows for the rigorous identification of TS conformations. By taking advantage of this possibility we have recently and accurately investigated the TS of lattice proteins and compared the results thus obtained with those resulting from the application of the simulational proxy of the phi-value analysis that, a priori, provides a less accurate picture of the TS. A major conclusion from this study is that the phi-value analysis is a powerful tool to pinpoint kinetically relevant residues in protein folding. However, a comparison of the TSs obtained via both methodologies shows no convincing relation between energetics (and kinetics) and TS structure.