Topological and energetic factors: what determines the structural details of the transition state ensemble and “en-route” intermediates for protein folding? an investigation for small globular proteins

Clementi, Cecilia; Nymeyer, Hugh; Onuchic, José N.

doi:10.1006/jmbi.2000.3693

Cited by 1,182 publications

(1,777 citation statements)

References 82 publications

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“…To address the "why is folding fast" question, recent theoretical discussions emphasize the funnel-like nature of the protein folding energy landscape as a solution to the Levinthal paradox 44,45 ( Figure 8b); and common Gō potentials are often used to model a relatively smooth funnel-like energy landscape. 12 We found that calorimetric two-state cooperativity can be consistent with the funnel-like landscapes of three-dimensional Gō models, provided some lattitude is allowed for empirical baseline subtractions. This is because in these native-centric models, the conformational populations with intermediate energies (enthalpies) -though not zero -are relatively low.…”

Section: Discussion: a Near-levinthal Scenario For Simple Two-state Pmentioning

confidence: 58%

Simple two‐state protein folding kinetics requires near‐levinthal thermodynamic cooperativity

2003

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Simple two-state folding kinetics of many small single-domain proteins are characterized by chevron plots with linear folding and unfolding arms consistent with an apparent two-state description of equilibrium thermodynamics. This phenomenon is hereby recognized as a nontrivial heteropolymer property capable of providing fundamental insight into protein energetics. Many current protein chain models, including common lattice and continuum Gō models with explicit native biases, fail to reproduce this generic protein property. Here we show that simple two-state kinetics is obtainable from models with a cooperative interplay between core burial and local conformational propensities or an extra strongly favorable energy for the native structure. These predictions suggest that intramolecular recognition in real two-state proteins is more specific than that envisioned by common Gō-like constructs with pairwise additive energies. The many-body interactions in the present kinetically two-state models lead to high thermodynamic cooperativity as measured by their van't Hoff to calorimetric enthalpy ratios, implying that the native and denatured conformational populations are well separated in enthalpy by a high free energy barrier. It has been observed experimentally that deviations from Arrhenius behavior are often more severe for folding than for unfolding. This asymmetry may be rationalized by one of the present modeling scenarios if the effective many-body cooperative interactions stablizing the native structure against unfolding is less dependent on temperature than the interactions that drive the folding kinetics.2

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Section: Discussion: a Near-levinthal Scenario For Simple Two-state Pmentioning

confidence: 58%

Simple two‐state protein folding kinetics requires near‐levinthal thermodynamic cooperativity

2003

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“…The influence of sequence-local interactions, a reflection of native state chain "topology" or "contact order", in accelerating folding has been developed into several models for protein folding, 20,21 and has been invoked as a major factor behind the successful prediction of folding pathways in globular proteins by simple funneled Go-models, 22 in which all native contacts are treated as uniformly favorable. [23][24][25] The success of Go-models in predicting the folding pathways of several proteins without energetic bias for specific contacts calls into question the importance of local stability in determining folding pathways, although a few recent simulations have indicated that folding is influenced by essential energetic components not accounted for by overall topological features. 24,26,27 In comparison to globular proteins, the structures of repeat proteins are highly conducive to testing for the existence of preferred pathways, and for determining how such pathways are specified.…”

Section: Introductionmentioning

confidence: 99%

Rerouting the Folding Pathway of the Notch Ankyrin Domain by Reshaping the Energy Landscape

Tripp

Barrick

2008

J. Am. Chem. Soc.

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The modular nature of repeat proteins has made them a successful target for protein design. Ankyrin repeat, TPR, and leucine rich repeat domains that have been designed solely on consensus information have been shown to have higher thermostability than their biological counterparts. We have previously shown that we can reshape the energy landscape of a repeat protein by adding multiple C-terminal consensus ankyrin repeats to the five N-terminal repeats of the Notch ankyrin domain. Here we explore how the folding mechanism responds to reshaping of the energy landscape. We have used analogous substitutions of a conserved alanine with glycine in each repeat to determine the distribution of structure in the transitions state ensembles of constructs containing one (Nank1-5C 1 ) and two consensus (Nank1-5C 2 ) ankyrin repeats. Whereas folding of the wild-type Notch ankyrin domain is slowed by substitutions in its central repeats, 1 folding of Nank1-5C 1 and Nank1-5C 2 is slowed by substitutions in the C-terminal repeats. Thus, the addition of C-terminal stabilizing repeats shifts the transition state ensemble towards the C-terminal repeats, rerouting the folding pathway of the ankyrin repeat domain. These findings indicate that for the Notch ankyrin domain, folding pathways are selected based on local energetics.

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“…How to satisfy these criteria for off-lattice chains is, by contrast, largely unknown, and therefore many current off-lattice models [5,[8][9][10][11][12][13][14] use Gō-type potentials [7] where non-native interactions are ignored. The use of the Gō approximation has some support from the finding that the native structure is a determinant for folding kinetics [15,16].…”

Section: Introductionmentioning

confidence: 99%

Folding of a small helical protein using hydrogen bonds and hydrophobicity forces

2002

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Abstract:A reduced protein model with five to six atoms per amino acid and five amino acid types is developed and tested on a three-helix-bundle protein, a 46-amino acid fragment from staphylococcal protein A. The model does not rely on the widely used Gō approximation where non-native interactions are ignored. We find that the collapse transition is considerably more abrupt for the protein A sequence than for random sequences with the same composition. The chain collapse is found to be at least as fast as helix formation. Energy minimization restricted to the thermodynamically favored topology gives a structure that has a root-mean-square deviation of 1.8Å from the native structure. The sequence-dependent part of our potential is pairwise additive. Our calculations suggest that fine-tuning this potential by parameter optimization is of limited use. *

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Topological and energetic factors: what determines the structural details of the transition state ensemble and “en-route” intermediates for protein folding? an investigation for small globular proteins

Cited by 1,182 publications

References 82 publications

Simple two‐state protein folding kinetics requires near‐levinthal thermodynamic cooperativity

Simple two‐state protein folding kinetics requires near‐levinthal thermodynamic cooperativity

Rerouting the Folding Pathway of the Notch Ankyrin Domain by Reshaping the Energy Landscape

Folding of a small helical protein using hydrogen bonds and hydrophobicity forces

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