Protein Folding Thermodynamics and Dynamics:  Where Physics, Chemistry, and Biology Meet

Shakhnovich, Eugene I.

doi:10.1021/cr040425u

Cited by 348 publications

(298 citation statements)

References 265 publications

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“…(5)). When t ≈ 10 −1 τ f the non-native single disulfide intermediates rearrange to form the more stable native [9][10][11][12][13][14][15][16][17][18][19][20][21][22] and [2][3][4][5][6][7][8][9][10][11][12][13][14][15] form early in the folding process when the ordering is determined by entropic considerations. The current experiments on BPTI are far too slow to detect these intermediates.…”

Section: Disulfide Bonds In Foldingmentioning

confidence: 99%

“…[5][6][7][8][9] In the last two decades, considerable progress has been made in attaining a global understanding of the mechanisms by which proteins fold thanks to breakthroughs in experiments, 10-12 theory, [13][14][15] and computations. [16][17][18][19] Fast folding experiments 4,11,[20][21][22] and single molecule methods [23][24][25] have begun to provide a direct glimpse into the initial stages of protein folding.…”

Section: Introductionmentioning

confidence: 99%

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Minimal Models for Proteins and RNA: From Folding to Function

Pincus

Cho

Hyeon

et al. 2008

Progress in Molecular Biology and Translational Science

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We present a panoramic view of the utility of coarse-grained (CG) models to study folding and functions of proteins and RNA. Drawing largely on the methods developed in our group over the last twenty years, we describe a number of key applications ranging from folding of proteins with disulfide bonds to functions of molecular machines. After presenting the theoretical basis that justifies the use of CG models, we explore the biophysical basis for the emergence of a finite number of folds from lattice models. The lattice model simulations of approach to the folded state show that non-native interactions are relevant only early in the folding process -a finding that rationalizes the success of structure-based models that emphasize native interactions. Applications of off-lattice C α and models that explicitly consider side chains (C α -SCM) to folding of β-hairpin and effects of macromolecular crowding are briefly discussed. Successful applications of a new class of off-lattice models, referred to as the Self- We also present two distinct models for RNA, namely, the Three Site Interaction (TIS) model and the SOP model, that probe forced unfolding and force quench refolding of a simple hairpin and Azoarcus ribozyme. The unfolding pathways of Azoarcus ribozyme depend on the loading rate, while constant force and constant loading rate simulations of the hairpin show that both forced-unfolding and force-quench refolding pathways are heterogeneous. The location of the transition state moves as force is varied. The predictions based on the SOP model show that force-induced unfolding pathways of the ribozyme can be dramatically changed by varying the loading rate. We conclude with a discussion of future prospects for the use of coarse-grained models in addressing problems of outstanding interest in biology.

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Section: Disulfide Bonds In Foldingmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Minimal Models for Proteins and RNA: From Folding to Function

Pincus

Cho

Hyeon

et al. 2008

Progress in Molecular Biology and Translational Science

View full text Add to dashboard Cite

show abstract

“…Considerable progress has been made in understanding the folding mechanisms of small, single-domain proteins by using a combination of theory and experiments (1)(2)(3)(4)(5). Folding of many of these proteins can be approximately described as being two-state-like, that is, their energy landscape does not exhibit pronounced local minima corresponding to partially folded or misfolded structures.…”

mentioning

confidence: 99%

Revealing the bifurcation in the unfolding pathways of GFP by using single-molecule experiments and simulations

Mickler

Dima

Dietz

et al. 2007

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

153

201

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Nanomanipulation of biomolecules by using single-molecule methods and computer simulations has made it possible to visualize the energy landscape of biomolecules and the structures that are sampled during the folding process. We use simulations and single-molecule force spectroscopy to map the complex energy landscape of GFP that is used as a marker in cell biology and biotechnology. By engineering internal disulfide bonds at selected positions in the GFP structure, mechanical unfolding routes are precisely controlled, thus allowing us to infer features of the energy landscape of the wild-type GFP. To elucidate the structures of the unfolding pathways and reveal the multiple unfolding routes, the experimental results are complemented with simulations of a self-organized polymer (SOP) model of GFP. The SOP representation of proteins, which is a coarse-grained description of biomolecules, allows us to perform forced-induced simulations at loading rates and time scales that closely match those used in atomic force microscopy experiments. By using the combined approach, we show that forced unfolding of GFP involves a bifurcation in the pathways to the stretched state. After detachment of an N-terminal ␣-helix, unfolding proceeds along two distinct pathways. In the dominant pathway, unfolding starts from the detachment of the primary N-terminal ␤-strand, while in the minor pathway rupture of the last, C-terminal ␤-strand initiates the unfolding process. The combined approach has allowed us to map the features of the complex energy landscape of GFP including a characterization of the structures, albeit at a coarse-grained level, of the three metastable intermediates.AFM experiments ͉ coarse-grained simulations ͉ cross-link mutants ͉ pathway bifurcation ͉ plasticity of energy landscape P rotein structures, which are astounding examples of selforganization in living systems, reach their folded states by navigating through a rugged energy landscape. Considerable progress has been made in understanding the folding mechanisms of small, single-domain proteins by using a combination of theory and experiments (1-5). Folding of many of these proteins can be approximately described as being two-state-like, that is, their energy landscape does not exhibit pronounced local minima corresponding to partially folded or misfolded structures. However, the folding energy landscapes of larger proteins, with complex topology, can be difficult to characterize because of the presence of multiple metastable intermediate structures (6,7). A detailed characterization of the structures of the intermediate states and the associated energetics is a challenge for the experimentalist. In part, the difficulty arises because complex proteins generally fold slowly and tend to aggregate in bulk experiments (8), a problem that can be avoided in mechanical unfolding of single proteins. Indeed, single-molecule mechanical methods have recently provided new possibilities for directly probing the energy landscapes of proteins and RNA because they can monito...

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“…With the rapid growth of computation power of computers, molecular mechanic (MM) force fields, such as CHARMM [1,2], AMBER [3,4], OPLS [5,6], GROMOS [7,8], and so on, have emerged and been used widely to study molecular liquids and biological systems [9][10][11]. Since nonpolarizable force fields only describe the electrostatic interactions solely in terms of fixed charges [12][13][14], a variety of polarizable force fields, such as AMOEBA [15,16], ABEEM/MM [17] and others [18][19][20], have been proposed including multipole moments and polarization response to the environments.…”

Section: Introductionmentioning

confidence: 99%

Coarse-grained simulations for organic molecular liquids based on Gay-Berne and electric multipole potentials

Shen

et al. 2012

J Mol Model

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Coarse-grained studies of CH 3 SH, CH 3 CHO and CHCl 3 liquids, based on anisotropic Gay-Berne (GB) and electric multipole potentials (EMP), demonstrate that the coarsegrained model is able to qualitatively reproduce the results obtained from the atomistic model (AMOEBA polarizable force field) and allows for significant saving in computation time. It should be pointed out that the accuracy of the coarse-grained model is very sensitive to how well the anisotropic GB particle is defined and how satisfactorily the EMP sites are chosen.

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Protein Folding Thermodynamics and Dynamics: Where Physics, Chemistry, and Biology Meet

Cited by 348 publications

References 265 publications

Minimal Models for Proteins and RNA: From Folding to Function

Minimal Models for Proteins and RNA: From Folding to Function

Revealing the bifurcation in the unfolding pathways of GFP by using single-molecule experiments and simulations

Coarse-grained simulations for organic molecular liquids based on Gay-Berne and electric multipole potentials

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