Protein Folding as a Diffusional Process

Abstract

A protein chain must move relative to the solvent molecules and explore many conformations when it folds from the extended unfolded state to the compact native state. Experimental and theoretical approaches suggest that diffusional processes in fact contribute to the kinetics of protein folding. We describe here how variations of the solvent viscosity can be employed to uncover the diffusional contributions to a folding reaction and assess the use of transition state theory and Kramers' rate theory for the analysis of protein folding reactions.

Trehalose-Mediated Inhibition of the Plasma Membrane H + -ATPase from Kluyveromyces lactis : Dependence on Viscosity and Temperature

“…Thus, the relative V max values (V max0 /V max ) were plotted against the relative viscosity values (/ 0 ) at each temperature tested (Fig. 5), and a linear dependence was observed as predicted (21,22). Thus, the trehalose-mediated inhibition of the H ϩ -ATPase is most likely caused by the increase in the viscosity of the solution.…”

“…Kramer's theory for reactions in solution, which is applicable to protein folding and enzyme kinetics, states that solution viscosity has a negative effect on the substrate probability of reaching the activated state and proceeding toward the product (21,22), i.e., increasing solvent viscosity should result in lower protein conformational motility and lower reaction rates. In this regard, it has been reported elsewhere that solvent viscosity is affected by changes in carbohydrate concentration and temperature (26,32).…”

“…In order to address the possible mechanism underlying the nonlinear inhibition of the H ϩ -ATPase by increasing trehalose concentrations (Fig. 1C), as well as the lack of V max inhibition by increasing temperature (Table 1), the data were analyzed as described by Jacob and Schmid (21) by using Kramer's theory (21,22). If a reaction obeys Kramer's theory, a linear relationship should be observed when the rate constant of the reaction is plotted against solution viscosity (20,21).…”

“…1C), as well as the lack of V max inhibition by increasing temperature (Table 1), the data were analyzed as described by Jacob and Schmid (21) by using Kramer's theory (21,22). If a reaction obeys Kramer's theory, a linear relationship should be observed when the rate constant of the reaction is plotted against solution viscosity (20,21). Thus, the relative V max values (V max0 /V max ) were plotted against the relative viscosity values (/ 0 ) at each temperature tested (Fig.…”

Computing the transition state populations in simple protein models

“…An alternative model would be an inverse dependence on macroscopic viscosity, following Kramer's rate expression, in conformity with the modeling of protein folding as a diffusion process. 22 But here we prefer the more microscopic strategy, since it discriminates between individual transitions on the basis of their three-dimensional structures. Figure 2 illustrates the time evolution of the native conformation at different values.…”