Protein Stability in Nanocages: A Novel Approach for Influencing Protein Stability by Molecular Confinement

Bolis, Dimos; Politou, Anastasia S.; Kelly, Geoff; Pastore, Annalisa; Temussi, Piero Andrea

doi:10.1016/j.jmb.2003.11.056

Cited by 76 publications

(81 citation statements)

References 48 publications

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“…The difference in the effect of confinement on transition-state free energy is due to the shape distribution within the transition state, as was recently noted (29). The stabilization of these proteins in various confinement conditions produces absolute changes in T f from 0 to 50°C, in the same range as experimental results on proteins confined within sol-gel matrices and gels (5,18,23). Our predictions for the scaling behavior can be further tested via experiments by localizing proteins in well-controlled matrices and pores.…”

Section: Discussionsupporting

confidence: 58%

“…Experimental and theoretical studies have shown that effects arising from excluded volume interactions either due to macromolecular crowding (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15) or localization (confinement) of the protein in a small volume (16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31), such as the ribosome tunnel (32) or a chaperonin cavity (33)(34)(35), can indeed have significant effects on folding. In the limit where the crowding particles are much bigger and heavier than the protein, the macromolecular crowding effects can be approximated by confinement; the shape and dimensions of the cavity will depend on the crowding concentration.…”

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confidence: 99%

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Thermodynamics and kinetics of protein folding under confinement

Mittal

Best

2008

Proc. Natl. Acad. Sci. U.S.A.

154

192

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Understanding the effects of confinement on protein stability and folding kinetics is important for describing protein folding in the cellular environment. We have investigated the effects of confinement on two structurally distinct proteins as a function of the dimension d c and characteristic size R of the confining boundary. We find that the stabilization of the folded state relative to bulk conditions is quantitatively described by R ؊␥ c, where the exponent ␥c is Ϸ5/3 independent of the dimension of confinement dc (cylindrical, planar, or spherical). Moreover, we find that the logarithm of the folding rates also scale as R ؊␥ c, with deviations only being seen for very small confining geometries, where folding is downhill; for both stability and kinetics, the dominant effect is the change in the free energy of the unfolded state. A secondary effect on the kinetics is a slight destabilization of the transition state by confinement, although the contacts present in the confined transition state are essentially identical to the bulk case. We investigate the effect of confinement on the position-dependent diffusion coefficients D(Q) for dynamics along the reaction coordinate Q (fraction of native contacts). The diffusion coefficients only change in the unfolded state basin, where they are increased because of compaction. macromolecular crowding ͉ course-grained simulation ͉ energy landscape ͉ diffusion P rotein folding in the cell occurs in a crowded, heterogeneous environment, a perturbation that may alter both the thermodynamics and kinetics of folding relative to observations made in dilute solutions. Experimental and theoretical studies have shown that effects arising from excluded volume interactions either due to macromolecular crowding (1-15) or localization (confinement) of the protein in a small volume (16-31), such as the ribosome tunnel (32) or a chaperonin cavity (33-35), can indeed have significant effects on folding. In the limit where the crowding particles are much bigger and heavier than the protein, the macromolecular crowding effects can be approximated by confinement; the shape and dimensions of the cavity will depend on the crowding concentration. This approach was shown to be applicable for a range of conditions in an insightful study by Cheung, Klimov, and Thirumalai (9). Specifically, they showed that the effect of crowding on protein-folding kinetics can be mimicked by confining the protein within a spherical cavity. The effect of crowding at low concentrations will be different from encapsulation in a spherical cavity and may be better represented by the weaker confining environment within a cylinder or between two planes. Because all of these confinement configurations may also appear naturally (e.g., cylindrical confinement for protein passage through a ribosome tunnel and planar confinement for proteins at interfaces or near surfaces), it is instructive to study the effects of varying the reduced dimensions due to confinement (d c ϭ 1, 2, and 3 for planar, cylindrical, and spherical...

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Section: Discussionsupporting

confidence: 58%

mentioning

confidence: 99%

Thermodynamics and kinetics of protein folding under confinement

Mittal

Best

2008

Proc. Natl. Acad. Sci. U.S.A.

154

192

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“…Two kinds of encapsulation are now widely used. The first is formed by nanoporous silica gels or glasses [32][33][34][35] or polyacrylamide gels [36]; the second is formed by sodium bis(2-ethylhexyl) sulfosuccinate (AOT) reverse micelles [37][38][39][40][41]. In both cases, the cage sizes can be controlled.…”

Section: Experimental Studies In the Test Tube Enhancement Of Foldingmentioning

confidence: 99%

Protein folding in confined and crowded environments

Zhou

2008

Archives of Biochemistry and Biophysics

152

137

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Confinement and crowding are two major factors that can potentially impact protein folding in cellular environments. Theories based on considerations of excluded volumes predict disparate effects on protein folding stability for confinement and crowding: confinement can stabilize proteins by over 10k B T but crowding has a very modest effect on stability. On the other hand, confinement and crowding are both predicted to favor conformations of the unfolded state which are compact, and consequently may increase the folding rate. These predictions are largely borne out by experimental studies of protein folding under confined and crowded conditions in the test tube. Protein folding in cellular environments is further complicated by interactions with surrounding surfaces and other factors. Concerted theoretical modeling and test-tube and in vivo experiments promise to elucidate the complexity of protein folding in cellular environments.The complexity of the cellular environments in which proteins function is increasingly been appreciated [1]. Potential impacts of two related, but distinct factors, confinement and macromolecular crowding, on protein folding are receiving extensive attention [2][3][4][5]. Confinement arises from encapsulation of proteins in compartments with dimensions on the scales of 10's to 100's Å, which are only moderately larger than the sizes of the proteins themselves. Examples of such compartments include the Anfinsen cage of chaperonins and the exit tunnel of ribosomes. Crowding refers to the exclusion of volumes to proteins of interest by the presence of other macromolecules. The aims of this paper are to discuss potential impacts of confinement and crowding on protein folding and to review the progress made by recent studies on protein folding in confined and crowded conditions and in cellular environments.

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“…[11][12][13][14][15] Several experiments have shown that the stability of the folded state, compared to the situation in the bulk, increases upon confinement. [16][17][18][19] In many cases the confinement-induced stability is adequately explained in terms of entropic destabilization of the unfolded states. [11][12][13] However, one can envision scenarios in which alterations in hydrophobic interactions in confined water can also destabilize the folded state.…”

Section: Introductionmentioning

confidence: 99%

Hydrophobic and Ionic Interactions in Nanosized Water Droplets

Vaitheeswaran

Thirumalai

2006

J. Am. Chem. Soc.

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A number of situations ranging from protein folding in confined spaces, lubrication in tight spaces, and chemical reactions in confined spaces require understanding water-mediated interactions. As an illustration of the profound effects of confinement on hydrophobic and ionic interactions we investigate the solvation of methane and methane decorated with charges in spherically confined water droplets. Free energy profiles for a single methane molecule in droplets, ranging in diameter (D) from 1 to 4 nm, show that the droplet surfaces are strongly favorable as compared to the interior. From the temperature dependence of the free energy in D = 3 nm, we show that this effect is entropically driven. The potentials of mean force (PMFs) between two methane molecules show that the solvent separated minimum in the bulk is completely absent in confined water, independent of the droplet size since the solute particles are primarily associated with the droplet surface. The tendency of methanes with charges (M q+ and M q− with q + = |q − | = 0.4e, where e is the electronic charge) to be pinned at the surface depends dramatically on the size of the water droplet. When D = 4 nm, the ions prefer the interior whereas for D < 4 nm the ions are localized at the surface, but with much less tendency than for methanes. Increasing the ion charge to e makes the surface strongly unfavorable. Reflecting the charge asymmetry of the water molecule, negative ions have a stronger preference for the surface compared to positive ions of the same charge magnitude. With increasing droplet size, the PMFs between M q+ and M q− show decreasing influence of the boundary due to the reduced tendency for surface solvation. We 1 also show that as the solute charge density decreases the surface becomes less unfavorable. The implications of our results for the folding of proteins in confined spaces are outlined.

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Protein Stability in Nanocages: A Novel Approach for Influencing Protein Stability by Molecular Confinement

Cited by 76 publications

References 48 publications

Thermodynamics and kinetics of protein folding under confinement

Thermodynamics and kinetics of protein folding under confinement

Protein folding in confined and crowded environments

Hydrophobic and Ionic Interactions in Nanosized Water Droplets

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