Protein folding mediated by solvation: Water expulsion and formation of the hydrophobic core occur after the structural collapse

Abstract

The interplay between structure-search of the native structure and desolvation in protein folding has been explored using a minimalist model. These results support a folding mechanism where most of the structural formation of the protein is achieved before water is expelled from the hydrophobic core. This view integrates water expulsion effects into the funnel energy landscape theory of protein folding. Comparisons to experimental results are shown for the SH3 protein. After the folding transition, a near-native intermediate with partially solvated hydrophobic core is found. This transition is followed by a final step that cooperatively squeezes out water molecules from the partially hydrated protein core.T he energy landscape theory and the funnel concept combined with a new generation of experiments provide a new framework for understanding the protein folding problem. According to this ''new view,'' the folding landscape for proteins (at least for small fast folding proteins) resembles a partially rough funnel riddled with traps where the protein can transiently reside (1-8). Recent theoretical and experimental evidence fully support this picture and suggests that, because the energetic roughness of the landscape is sufficiently small (low level of energetic frustration), the global characteristics of the structural heterogeneity observed in the transition state ensemble for two-state fast folding proteins are most strongly determined by the native state topology. For this reason, theoretical energetically unfrustrated models have been shown to reproduce nearly all experimental results for the global geometrical features of the transition state ensemble of a large number of real proteins, which are two-state or three-state folders, on whose native structures they are based (9-24).Some concerns have been raised, however, about the applicability of these models. For example, solvent effects are incorporated implicitly into the energetic interactions between residues. Such implicit equilibrium models for solvation are unable to capture effects such as desolvation of the hydrophobic core; therefore, understanding the potential of mean force for the interaction between solutes in an aqueous solvent attracts the attention of many research groups (25-30). The potential of mean force (PMF) between two methane-like particles exhibit two minima-a contact minimum at the van der Waals distance between the particles and a solvent-separated minimum. The two minima are separated by a desolvation barrier with a width of approximately one water molecule diameter. Recently, Hillson et al. (31,32) advertised the importance of the desolvation effect by taking into account the process of expelling a water molecule in a pairwise interaction between hydrophobic particles. Assuming that the time scale for water penetration and escape are faster than the contact formation in proteins (33), the shape of this potential energy function implies that there are free-energy costs for protein (de)solvation (27). The time scale separation ass...

Simple two‐state protein folding kinetics requires near‐levinthal thermodynamic cooperativity

“…18 This we have recently demonstrated in several examples, 7,8 including lattice and continuum (off-lattice) models as well as models with a rudimentary implicit-solvent treatment of desolvation barriers. 8,19 Thus, the inability of common Gō-like constructs to predict simple two-state folding/unfolding kinetics is not an artifact restricted only to lattice Gō models. Most likely, it is a fundamental problem arising from the additive nature of common Gō-like interaction schemes.…”

Structural and kinetic modeling of an activating helix switch in the rhodopsin-transducin interface

“…Our analysis further indicates that these hydrogen bonding networks are extended by interfacial water (Figs. S2 and S3), which is known to facilitate the transition between different conformational states of proteins (34)(35)(36). Thus, interfacial water may allow the necessary sliding motion of ␣5 in its crevice.…”

Dissecting the THz spectrum of liquid water from first principles via correlations in time and space

“…In recent years, however, the role of water has been revealed to be far more active than just being an inert solvent (2). Water molecules at protein/water interfaces, dubbed "hydration water" or "interfacial water," have been shown not just to thermodynamically stabilize the native structure of biomacromolecules, but also to enhance their dynamical flexibility needed for efficient enzymatic catalysis and especially for the folding process that leads to the active structure of such molecules (4)(5)(6)(7). Solvation was shown to be a key feature for protein function (8), with the coupling between protein and water dynamics (9) as an important ingredient to understand protein folding and binding.…”