The experimental survey of protein-folding energy landscapes

Oliveberg, Mikael; Wolynes, Peter G.

doi:10.1017/s0033583506004185

Cited by 272 publications

(303 citation statements)

References 162 publications

(187 reference statements)

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“…At the other end of the complexity spectrum, energy landscapes [8][9][10] represent folding using a detailed multidimensional reaction coordinate system in which multiple partly folded states are related by their respective energies (either as free or internal energies). By definition, such a coordinate system has the capacity to depict the details of folding pathways, competition among parallel routes and heterogeneity among ensembles of partly folded conformations.…”

Section: Introductionmentioning

confidence: 99%

Predicting repeat protein folding kinetics from an experimentally determined folding energy landscape

Street

Barrick

2008

Protein Science

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The Notch ankyrin domain is a repeat protein whose folding has been characterized through equilibrium and kinetic measurements. In previous work, equilibrium folding free energies of truncated constructs were used to generate an experimentally determined folding energy landscape (Mello and Barrick, Proc Natl Acad Sci USA 2004;101:14102-14107). Here, this folding energy landscape is used to parameterize a kinetic model in which local transition probabilities between partly folded states are based on energy values from the landscape. The landscape-based model correctly predicts highly diverse experimentally determined folding kinetics of the Notch ankyrin domain and sequence variants. These predictions include monophasic folding and biphasic unfolding, curvature in the unfolding limb of the chevron plot, population of a transient unfolding intermediate, relative folding rates of 19 variants spanning three orders of magnitude, and a change in the folding pathway that results from C-terminal stabilization. These findings indicate that the folding pathway(s) of the Notch ankyrin domain are thermodynamically selected: the primary determinants of kinetic behavior can be simply deduced from the local stability of individual repeats.

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Section: Introductionmentioning

confidence: 99%

Predicting repeat protein folding kinetics from an experimentally determined folding energy landscape

Street

Barrick

2008

Protein Science

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“…The simplest system to study, and the one that has produced the most insights, is a protein exhibiting 2-state behavior (1)(2)(3)(4)(5)(6)(7). A 2-state protein has only 2-populations of molecules in equilibrium and at all times in kinetic experiments-folded and unfolded.…”

mentioning

confidence: 99%

Experimental determination of upper bound for transition path times in protein folding from single-molecule photon-by-photon trajectories

Chung

Louis²,

Eaton³

2009

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

271

304

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Transition paths are a uniquely single-molecule property not yet observed for any molecular process in solution. The duration of transition paths is the tiny fraction of the time in an equilibrium single-molecule trajectory when the process actually happens. Here, we report the determination of an upper bound for the transition path time for protein folding from photon-by-photon trajectories. FRET trajectories were measured on single molecules of the dyelabeled, 56-residue 2-state protein GB1, immobilized on a glass surface via a biotin-streptavidin-biotin linkage. Characterization of individual emitted photons by their wavelength, polarization, and absolute and relative time of arrival after picosecond excitation allowed the determination of distributions of FRET efficiencies, donor and acceptor lifetimes, steady state polarizations, and waiting times in the folded and unfolded states. Comparison with the results for freely diffusing molecules showed that immobilization has no detectable effect on the structure or dynamics of the unfolded protein and only a small effect on the folding/unfolding kinetics. Analysis of the photon-by-photon trajectories yields a transition path time <200 s, >10,000 times shorter than the mean waiting time in the unfolded state (the inverse of the folding rate coefficient). Szabo's theory for diffusive transition paths shows that this upper bound for the transition path time is consistent with previous estimates of the Kramers preexponential factor for the rate coefficient, and predicts that the transition path time is remarkably insensitive to the folding rate, with only a 2-fold difference for rate coefficients that differ by 10 5 -fold.A detailed description and understanding of mechanisms of protein folding has been one of the great challenges to biophysical science. The simplest system to study, and the one that has produced the most insights, is a protein exhibiting 2-state behavior (1-7). A 2-state protein has only 2-populations of molecules in equilibrium and at all times in kinetic experiments-folded and unfolded. In ensemble folding experiments kinetics are studied by rapidly changing solution conditions, e.g., the temperature or denaturant concentration, and monitoring the relaxation of the 2 populations to their new equilibrium ratio with probes such as fluorescence, circular dichroism or infrared spectroscopy. Single molecule kinetics, however, can be studied at equilibrium. As can be seen from the schematic of a trajectory in Fig. 1, the dynamical nature of equilibrium is dramatically demonstrated when observing Förster resonance energy transfer (FRET) in a single-molecule fluorescence experiment. There are fluctuations due to shot noise about a mean value in each state, interrupted by what appear to be instantaneous jumps in FRET efficiency signaling folding or unfolding. The residence or waiting times in each state are exponentially distributed, with the mean time in the unfolded and folded segments of the trajectories corresponding to the inverse of the folding and ...

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“…Protein folding is limited by the energy landscape barriers (Oliveberg and Wolynes 2005;Hartl et al 2011), which guide folding intermediates down favorable path(s) required to achieve a functional fold . The polypeptide chain frequently occupies intermediate metastable states that are necessary to achieve function.…”

Section: Proteostasis Biologymentioning

confidence: 99%

“…For example, COPII and clathrin "see" thousands of cargo clients during recruitment from the ER or plasma membrane, respectively, yet each cargo ultimately programs its own destiny in the TPN mosaic through directed interaction with the TPN biology using trafficking codes embedded in its primary sequence, but presented in the context of its higher-order secondary, tertiary, and quaternary structure. Indeed, TRaCKS likely direct membrane compartment architectures through the same basic rules that facilitate the energetics of protein folding (Oliveberg and Wolynes 2005;Wiseman et al 2007b;Hutt et al 2009;Powers et al 2009Powers et al , 2012, where the kinetic and thermodynamic properties of the cargo fold will dictate the steady-state formation of endomembrane boundaries (Fig. 3B) (Hutt et al 2009;Powers et al 2009).…”

Section: Integrating Proteostasis and Membrane Trafficking Biologymentioning

confidence: 99%

Expanding Proteostasis by Membrane Trafficking Networks

Hutt

Balch

2013

Cold Spring Harbor Perspectives in Biology

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The folding biology common to all three kingdoms of life (Archaea, Bacteria, and Eukarya) is proteostasis. The proteostasis network (PN) functions as a "cloud" to generate, protect, and degrade the proteome. Whereas microbes (Bacteria, Archaea) have a single compartment, Eukarya have numerous subcellular compartments. We examine evidence that Eukarya compartments use coat, tether, and fusion (CTF) membrane trafficking components to form an evolutionarily advanced arm of the PN that we refer to as the "trafficking PN" (TPN). We suggest that the TPN builds compartments by generating a mosaic of integrated cargo-specific trafficking signatures (TRaCKS). TRaCKS control the temporal and spatial features of protein-folding biology based on the Anfinsen principle that the local environment plays a critical role in managing protein structure. TPN-generated endomembrane compartments apply a "quinary" level of structural control to modify the secondary, tertiary, and quaternary structures defined by the primary polypeptide-chain sequence. The development of Anfinsen compartments provides a unifying foundation for understanding the purpose of endomembrane biology and its capacity to drive extant Eukarya function and diversity.

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The experimental survey of protein-folding energy landscapes

Cited by 272 publications

References 162 publications

Predicting repeat protein folding kinetics from an experimentally determined folding energy landscape

Predicting repeat protein folding kinetics from an experimentally determined folding energy landscape

Experimental determination of upper bound for transition path times in protein folding from single-molecule photon-by-photon trajectories

Expanding Proteostasis by Membrane Trafficking Networks

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