Protein folding is slaved to solvent motions

Abstract

Proteins, the workhorses of living systems, are constructed from chains of amino acids, which are synthesized in the cell based on the instructions of the genetic code and then folded into working proteins. The time for folding varies from microseconds to hours. What controls the folding rate is hotly debated. We postulate here that folding has the same temperature dependence as the ␣-fluctuations in the bulk solvent but is much slower. We call this behavior slaving. Slaving has been observed in folded proteins: Large-scale protein motions follow the solvent fluctuations with rate coefficient k␣ but can be slower by a large factor. Slowing occurs because large-scale motions proceed in many small steps, each determined by k␣. If conformational motions of folded proteins are slaved, so a fortiori must be the motions during folding. The unfolded protein makes a Brownian walk in the conformational space to the folded structure, with each step controlled by k␣. Because the number of conformational substates in the unfolded protein is extremely large, the folding rate coefficient, kf, is much smaller than k␣. The slaving model implies that the activation enthalpy of folding is dominated by the solvent, whereas the number of steps nf ‫؍‬ k␣͞kf is controlled by the number of accessible substates in the unfolded protein and the solvent. Proteins, however, undergo not only ␣-but also ␤-fluctuations. These additional fluctuations are local protein motions that are essentially independent of the bulk solvent fluctuations and may be relevant at late stages of folding.folding energy landscape ͉ fractional viscosity dependence ͉ internal viscosity ͉ Maxwell relation ͉ protein-solvent interaction P roteins in cells fold and unfold continuously. Consequently, an understanding of folding rates is key. The distribution and strength of contacts in the native state is one ingredient that influences the rate of folding (1). A second ingredient is the effect of the solvent, because protein motions are intimately linked to the motions of the environment. Our slaving model quantifies the linkage. The model is based on three concepts: Proteins assume a large number of different conformations or substates (2), their organization is described by a hierarchic energy landscape (3), and large-scale protein fluctuations follow the ␣-relaxation (Debye or dielectric relaxation) in the bulk solvent (4-6). Here we propose that these concepts also are valid for folding and that they lead to the model pictured in Fig. 1. Fig. 1a is a cartoon of folding and a 1D cross-section through the high-dimensional energy landscape. Fig. 1b is a 2D cross-section.

Mean-squared atomic displacements in hydrated lysozyme, native and denatured

“…This can be intuitively understood as a result of unfolding of the initially much more compact native protein into a more random-coil-like the conformation. Although we do not suggest that the conformational flexibility that accompanies enhanced atomic dynamics is not important for biological activity [44][45][46], our data indicate that the onset of the transition in the mean-squared displacement alone is not sufficient for explaining the onset of biological function. It is widely believed that the transition to anharmonicity is driven by the hydration water, which "slaves" the motions of biomolecules.…”

Fluorescent Labeling Preserving OCP Photoactivity Reveals Its Reorganization during the Photocycle

“…Indeed, the dependence of protein folding rates on solvent viscosity is described by the Kramers theory, which predicts an inverse relation of the transition rate on viscosity and can formally be applied to the specific case of OCP photoconversion (37,38). Hence, we measured the dependence of OCP transition rates on solvent viscosity that was varied by changing glycerol content in the buffer solution (39,40).…”

Biocatalyst activity in nonaqueous environments correlates with centisecond-range protein motions

“…It is noteworthy that numerous previous studies, including a recent study by our laboratory (33), provide evidence of correlations between fast solvent dynamics and molecular events evident on slower timescales [e.g., substrate dissociation in myoglobin (34); protein folding of cytochrome c, protein L, and human serum albumin (35,36); and enzyme activity (37,38)]. The intimate collusion between fast solvent dynamics and slow protein motion is referred to as solvent slaving and has been reported for many classes of proteins (39,40).…”