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. 2008 Oct;95(7):3391-9.
doi: 10.1529/biophysj.108.131037. Epub 2008 Jul 3.

Potential for modulation of the hydrophobic effect inside chaperonins

Jeremy L England  1 , Vijay S Pande
Affiliations

Potential for modulation of the hydrophobic effect inside chaperonins

Jeremy L England et al. Biophys J. 2008 Oct.

Abstract

Despite the spontaneity of some in vitro protein-folding reactions, native folding in vivo often requires the participation of barrel-shaped multimeric complexes known as chaperonins. Although it has long been known that chaperonin substrates fold upon sequestration inside the chaperonin barrel, the precise mechanism by which confinement within this space facilitates folding remains unknown. We examine the possibility that the chaperonin mediates a favorable reorganization of the solvent for the folding reaction. We discuss the effect of electrostatic charge on solvent-mediated hydrophobic forces in an aqueous environment. Based on these physical arguments, we construct a simple, phenomenological theory for the thermodynamics of density and hydrogen-bond order fluctuations in liquid water. Within the framework of this model, we investigate the effect of confinement inside a chaperonin-like cavity on the configurational free energy of water by calculating solvent free energies for cavities corresponding to the different conformational states in the ATP-driven catalytic cycle of the prokaryotic chaperonin GroEL. Our findings suggest that one function of chaperonins may involve trapping unfolded proteins and subsequently exposing them to a microenvironment in which the hydrophobic effect, a crucial thermodynamic driving force for folding, is enhanced.

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Figures

FIGURE 1
FIGURE 1
Equilibrium order parameters formula image and formula image inside spherical shells were calculated using formula image formula image and formula image All data reported in this study use the same parameters for the free-energy functional. Units of length are set by ℓ, the size of a water molecule (∼4 Å). Order parameters are unitless, and are measured as a fraction of their bulk value, whereas formula image and formula image have units of kcal/mol/formula image and formula image and formula image have units of kcal/mol/ℓ. (Left) Liquid density (darker shading corresponding to lesser density) is plotted in the space between the surface of the protein (red, unfolded; green, folded) and the cavity (red, hydrophobic; blue, hydrophilic) wall for an unfolded protein inside an “open” hydrophobic cavity (top), an unfolded protein inside a “closed” hydrophilic cavity (middle), and a folded protein in a closed cavity (bottom). Gold arrows indicate the direction of solvent-mediated force between the two surfaces (Fig. 2) (Right) Liquid density (green curves) and hydrogen-bond order (orange curves) are plotted as a fraction of their bulk values. At a hydrophobic surface, there is a loss of hydrogen bonding and a depletion of liquid density. In contrast, at a highly hydrophilic surface, there is an elevation in liquid density and a greater amount of hydrogen bonding.
FIGURE 2
FIGURE 2
Solvent free energy, estimated in formula image per unit area of surface, is plotted as a function of separation formula image for pairs of horizontal plates. Distance is measured in units of the shorter correlation length of the Landau theory, about equivalent to the size of a few water molecules. Between two hydrophobic plates (dark gray curve), the solvent mediates an attractive force that grows stronger with proximity. Between a hydrophobic plate and a highly hydrophilic plate (gray curve), there is a weaker repulsive force. Between two hydrophilic plates, the force is essentially nonexistent (light gray curve).
FIGURE 3
FIGURE 3
The change in folding free energy formula image is defined as the difference between the free energy of folding under confinement formula image and the free energy of folding in bulk solution formula image The fractional change in this solvent free energy of folding is plotted as a function of confinement radius formula image for formula image less the width formula image of the interaction shell at each surface. Length is measured in units of the shorter correlation length of the theory of solvent fluctuations described in Eq. 3. When the protein is confined in the largely hydrophobic open GroEL cavity (dark gray curve), the folded state is more destabilized as the degree of confinement increases. However, when confined in the closed, highly hydrophilic chaperonin cavity (light gray curve), stabilization of the folded state increases with degree of confinement.
FIGURE 4
FIGURE 4
A model of chaperonin action. Hydrophobic forces cause an unfolded (red) protein to bind to the wall of the open (red) GroEL barrel (a → b). Upon formation of a closed (blue) complex containing GroES and ATP, rearrangements in the barrel present a hydrophilic surface to the interior that repels the substrate into the center of the cavity (b → c). Because of this repulsion, the free energy formula image of folding to the native (green) conformation inside the cavity (c → d) is more negative than the folding free energy formula image out in bulk solution (a → e). The hydrolysis of ATP therefore drives a local enhancement of the hydrophobic effect inside the chaperonin.
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