Ribosome exit tunnel can entropically stabilize α-helices

Ziv, Guy; Haran, Gilad; Thirumalai, D.

doi:10.1073/pnas.0508234102

Cited by 141 publications

(136 citation statements)

References 33 publications

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“…Simulations using spheres as confinement do not qualitatively change the results with respect to the cases using spherical cylinders (10,22,23). Although study using an infinite cylinder shows different effects of the confinement on folding (21), this kind of confinement is different from those using spheres or spherical cylinders due to the absence of restriction along the axis. Furthermore, a study on the molecular crowding effect on folding of globular proteins suggested that, to depict a rather crowded in vivo environment, the optimal cavity to host protein molecule may be cylindrical (11).…”

Section: Resultsmentioning

confidence: 80%

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Confinement effects on the kinetics and thermodynamics of protein dimerization

Wang

Levy

et al. 2009

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

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In the cell, protein complexes form by relying on specific interactions between their monomers. Excluded volume effects due to molecular crowding would lead to correlations between molecules even without specific interactions. What is the interplay of these effects in the crowded cellular environment? We study dimerization of a model homodimer when the mondimers are free and when they are tethered to each other. We consider a structured environment: Two monomers first diffuse into a cavity of size L and then fold and bind within the cavity. The folding and binding are simulated by using molecular dynamics based on a simplified topology based model. The confinement in the cell is described by an effective molecular concentration C ϳ L ؊3 . A two-state coupled folding and binding behavior is found. We show the maximal rate of dimerization occurred at an effective molecular concentration C op Ӎ 1 mM, which is a relevant cellular concentration. In contrast, for tethered chains the rate keeps at a plateau when C < C op but then decreases sharply when C > C op . For both the free and tethered cases, the simulated variation of the rate of dimerization and thermodynamic stability with effective molecular concentration agrees well with experimental observations. In addition, a theoretical argument for the effects of confinement on dimerization is also made. molecular crowding ͉ folding and binding ͉ effective molecular concentration ͉ Arc homodimer monolayer ͉ native topology-based models

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Section: Resultsmentioning

confidence: 80%

“…Other shapes, such as a sphere or an infinite cylinder, were also used previously to study the confinement/crowding effect on protein folding (10,11,13,(21)(22)(23). Simulations using spheres as confinement do not qualitatively change the results with respect to the cases using spherical cylinders (10,22,23).…”

Section: Resultsmentioning

confidence: 99%

Confinement effects on the kinetics and thermodynamics of protein dimerization

Wang

Levy

et al. 2009

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

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“…Confinement has been previously treated both analytically and via simulation using polymer physics models (3)(4)(5)(6)(7)(8)(9)(10). These models predict that by excluding more extended structures confinement reduces the conformational entropy of the unfoldedstate ensemble.…”

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confidence: 99%

“…Specifically, Ziv et al (10) have suggested that for a small helical peptide helix formation is stabilized upon confinement to a cylindrical cavity. These results were explained in terms of polymer entropy arguments as described above.…”

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confidence: 99%

Protein folding under confinement: A role for solvent

Lucent

Vishal²,

Pande

2007

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

155

149

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Although most experimental and theoretical studies of protein folding involve proteins in vitro, the effects of spatial confinement may complicate protein folding in vivo. In this study, we examine the folding dynamics of villin (a small fast folding protein) with explicit solvent confined to an inert nanopore. We have calculated the probability of folding before unfolding (Pfold) under various confinement regimes. Using Pfold correlation techniques, we observed two competing effects. Confining protein alone promotes folding by destabilizing the unfolded state. In contrast, confining both protein and solvent gives rise to a solvent-mediated effect that destabilizes the native state. When both protein and solvent are confined we see unfolding to a compact unfolded state different from the unfolded state seen in bulk. Thus, we demonstrate that the confinement of solvent has a significant impact on protein kinetics and thermodynamics. We conclude with a discussion of the implications of these results for folding in confined environments such as the chaperonin cavity in vivo.chaperonin mechanism ͉ explicit solvent ͉ distributed computing ͉ molecular dynamics H ow proteins fold into a unique native structure is an important unanswered question. There have been a number of experiments and computer simulations that have provided insight into the mechanism by which folding occurs (1, 2). Most of these experiments and simulations measure the dynamics of proteins in infinite dilution. However, bulk solvent is different from the cellular environment in which proteins truly fold. In vivo, protein dynamics occur in the context of the crowded cellular milieu and in confined spaces such as the chaperonin cavity, the proteosome, the ribosome exit tunnel, the translocon, etc. When considering these factors it is reasonable to assume that proteins may experience different energy landscapes when folding in vivo than in bulk, and these differences may constitute a significant piece of the folding puzzle.Confinement has been previously treated both analytically and via simulation using polymer physics models (3-10). These models predict that by excluding more extended structures confinement reduces the conformational entropy of the unfoldedstate ensemble. This restriction leads to the relative stabilization of the folded state. These models are in qualitative accord with recent experiments that have shown accelerated folding of small proteins in chaperonin mutants possessing decreased cavity volume (11). Despite the elegance and intuitiveness of these models, they omit details that may be important when thinking of folding in vivo.For example, it is known that solvent plays a critical role in protein folding, as most of the free energy for folding comes from maximizing solvent entropy (because of the molecular nature of hydrophobicity). Polymer models for confined folding do not consider the effect of confinement on the solvent and its subsequent effects on protein stability. Although explicit solvent complicates analytical models a...

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“…However, further results of biochemical, microscopical and computational experiments clearly showed that this tunnel participates actively in nascent chain progression, arrest and cellular signalling (e.g. Gabashvili et al 2001;Gong & Yanofsky 2002;Nakatogawa & Ito 2002;Berisio et al 2003Berisio et al , 2006Gilbert et al 2004;Johnson & Jensen 2004;Woolhead et al 2004Woolhead et al , 2006Amit et al 2005;Ziv et al 2005;Cruz-Vera et al 2006;Kaiser et al 2006;Mankin 2006;Mitra et al 2006;Tenson & Mankin 2006;Voss et al 2006;Deane et al 2007;Schaffitzel & Ban 2007;Petrone et al 2008), and that in eubacteria, nascent proteins progress along this tunnel and emerge into a shelter formed by chaperones, preventing aggregation and misfolding Schluenzen et al 2005).…”

Section: Introductionmentioning

confidence: 99%

Large facilities and the evolving ribosome, the cellular machine for genetic-code translation

Yonath

2009

J. R. Soc. Interface.

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Well-focused X-ray beams, generated by advanced synchrotron radiation facilities, yielded high-resolution diffraction data from crystals of ribosomes, the cellular nano-machines that translate the genetic code into proteins. These structures revealed the decoding mechanism, localized the mRNA path and the positions of the tRNA molecules in the ribosome and illuminated the interactions of the ribosome with initiation, release and recycling factors. They also showed that the ribosome is a ribozyme whose active site is situated within a universal symmetrical region that is embedded in the otherwise asymmetric ribosome structure. As this highly conserved region provides the machinery required for peptide bond formation and for ribosome polymerase activity, it may be the remnant of the proto-ribosome, a dimeric prebiotic machine that formed peptide bonds and non-coded polypeptide chains. Synchrotron radiation also enabled the determination of structures of complexes of ribosomes with antibiotics targeting them, which revealed the principles allowing for their clinical use, revealed resistance mechanisms and showed the bases for discriminating pathogens from hosts, hence providing valuable structural information for antibiotics improvement.

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Ribosome exit tunnel can entropically stabilize α-helices

Abstract: Several experiments have suggested that newly synthesized polypeptide chains can adopt helical structures deep within the ribosome exit tunnel. We hypothesize that confinement in the roughly cylindrical tunnel can entropically stabilize ␣-helices.

Cited by 141 publications

References 33 publications

Confinement effects on the kinetics and thermodynamics of protein dimerization

Confinement effects on the kinetics and thermodynamics of protein dimerization

Protein folding under confinement: A role for solvent

Large facilities and the evolving ribosome, the cellular machine for genetic-code translation

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