Analysis of Two-State Folding Using Parabolic Approximation III: Non-Arrhenius Kinetics of FBP28 WW Part-I

A model which treats the denatured and the native conformers as being confined to harmonic Gibbs energy wells has been used to analyse the non-Arrhenius behaviour of spontaneously-folding fixed two-state systems. The results demonstrate that when pressure and solvent are constant: ( i ) a two-state system is physically defined only for a finite temperature range; ( ii ) irrespective of the primary sequence, the 3-dimensional structure of the native conformer, the residual structure in the denatured state, and the magnitude of the folding and unfolding rate constants, the equilibrium stability of a two-state system is a maximum when its denatured conformers bury the least amount of solvent accessible surface area (SASA) to reach the activated state; ( iii ) the Gibbs barriers to folding and unfolding are not always due to the incomplete compensation of the activation enthalpies and entropies; ( iv ) the difference in heat capacity between the reaction-states is due to both the size of the solvent-shell and the non-covalent interactions; ( v ) the position of the transition state ensemble along the reaction coordinate (RC) depends on the choice of the RC; and ( vi ) the atomic structure of the transiently populated reaction-states cannot be inferred from perturbation-induced changes in their energetics.