Sparsely populated folding intermediates of the Fyn SH3 domain: Matching native-centric essential dynamics and experiment

Ollerenshaw, Jason E.; Kaya, Hüseyin; Chan, Hue Sun; Kay, Lewis E.

doi:10.1073/pnas.0404436101

Cited by 32 publications

(34 citation statements)

References 51 publications

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“…Recent progress in NMR techniques has made it possible to obtain detailed structural information on "invisible," low-populated protein states (48,49). In view of the agreement with experiment achieved here and our approach's previous success in predicting specific nonnative interactions in the folding transition state of Fyn SH3 mutants (27), the predicted misfolded and mispacked Top7 structures (Figs.…”

Section: Discussionsupporting

confidence: 53%

Competition between native topology and nonnative interactions in simple and complex folding kinetics of natural and designed proteins

Zhang

Chan²

2010

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

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We compared folding properties of designed protein Top7 and natural protein S6 by using coarse-grained chain models with a mainly native-centric construct that accounted also for nonnative hydrophobic interactions and desolvation barriers. Top7 and S6 have similar secondary structure elements and are approximately equal in length and hydrophobic composition. Yet their experimental folding kinetics were drastically different. Consistent with experiment, our simulated folding chevron arm for Top7 exhibited a severe rollover, whereas that for S6 was essentially linear, and Top7 model kinetic relaxation was multiphasic under strongly folding conditions. The peculiar behavior of Top7 was associated with several classes of kinetic traps in our model. Significantly, the amino acid residues participating in nonnative interactions in trapped conformations in our Top7 model overlapped with those deduced experimentally. These affirmations suggest that the simple ingredients of native topology plus sequence-dependent nonnative interactions are sufficient to account for some key features of protein folding kinetics. Notably, when nonnative interactions were absent in the model, Top7 chevron rollover was not correctly predicted. In contrast, nonnative interactions had little effect on the quasi linearity of the model folding chevron arm for S6. This intriguing distinction indicates that folding cooperativity is governed by a subtle interplay between the sequence-dependent driving forces for native topology and the locations of favorable nonnative interactions entailed by the same sequence. Constructed with a capability to mimic this interplay, our simple modeling approach should be useful in general for assessing a designed sequence's potential to fold cooperatively.T he study of protein folding is important not only for deciphering the folding process and how misfolding can occur. The principles developed in theoretical investigations of folding (1-3) have provided insights into a broad range of molecularrecognition phenomena and dynamic behaviors in biology. Recent examples include protein-protein interactions (4), function of biomolecular machines (5), effects of desolvation in selfassembly (6, 7), and switch-like properties in binding (8). Among naturally evolved proteins, many fold cooperatively in a twostate-like manner (9), which is a remarkable feat from the vantage point of polymer physics (10). Although not all natural proteins share this property (11), its commonality argues that folding cooperativity may serve crucial biological functions such as guarding against harmful aggregation (12).If cooperative folding can be a desirable trait under certain circumstances, a fundamental question arises: Can all folded globular structures attain a high degree of folding cooperativity? A revealing case is the designed protein Top7 (13), which folds to a de novo target structure that did not exist previously in the Protein Data Bank (PDB) but does so noncooperatively (14, 15). One possible reason for Top7's failure to fold coo...

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Section: Discussionsupporting

confidence: 53%

Competition between native topology and nonnative interactions in simple and complex folding kinetics of natural and designed proteins

Zhang

Chan²

2010

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

Self Cite

150

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“…A comparison of the Spc-SH3 intermediates with those identified for two variants of Fyn-SH3 mutated at position 48 34,40 (G48M and G48V) reveals striking similarities. The Fyn intermediates also have the native topology defined, and in terms of secondary structure content, their most nativelike region also encompasses strands β 3 and β 4 .…”

Section: Structural Characterization Of the Intermediate Statesmentioning

confidence: 88%

“…Indeed, and precisely because they do not incorporate nonnative interactions, Gō potentials are not able to correctly model misfolding processes leading to compact nonnative states 33 and, more generally, regions of the free energy landscape where nonnative interactions play an important role. They should, however, be able to capture native-like intermediates similar to those reported for Fyn-SH3 34 and other proteins. 22,23 Here, we make a detailed assessment of the impact of amyloidogenic mutations on the dynamics and equilibrium folding of the Spc-SH3 domain via discrete molecular dynamics (DMD) simulations of a hybrid model that combines a simple discontinuous Gō potential with an all-atom representation of the protein.…”

Section: Introductionmentioning

confidence: 90%

Identification of a Conserved Aggregation-Prone Intermediate State in the Folding Pathways of Spc-SH3 Amyloidogenic Variants

Krobath

Estácio

Faísca

et al. 2012

Journal of Molecular Biology

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“…57 A similar analysis has also been reported for microtubule components, 58 Trp repressor, calmodulin, calbindin, HIV-1 protease, and troponin C 59 in which localized large conformational changes have been shown to arise due to collective normal mode oscillations of the entire protein at specific frequencies. MD simulations of acetylcholinesterase, 60 DNA binding LacI and PurR proteins, 61 integrins, 62 calmodulin, 63,64 metalloproteins, 65 and the folding of the SH3 domain 66 clearly indicate the importance of domain flexibility in the functioning of these systems. With the rapidly increasing number of structures becoming available due to structural genomics initiatives, automated methods to identify domains and linkers 67,68 are expected to become increasingly important in domain flexibility studies.…”

Section: Computational Detection Of Domains Linkers and Their Movemmentioning

confidence: 99%

Control of protein functional dynamics by peptide linkers

2005

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Control of structural flexibility is essential for the proper functioning of a large number of proteins and multiprotein complexes. At the residue level, such flexibility occurs due to local relaxation of peptide bond angles whose cumulative effect may result in large changes in the secondary, tertiary or quaternary structures of protein molecules. Such flexibility, and its absence, most often depends on the nature of interdomain linkages formed by oligopeptides. Both flexible and relatively rigid peptide linkers are found in many multidomain proteins. Linkers are thought to control favorable and unfavorable interactions between adjacent domains by means of variable softness furnished by their primary sequence. Large-scale structural heterogeneity of multidomain proteins and their complexes, facilitated by soft peptide linkers, is now seen as the norm rather than the exception. Biophysical discoveries as well as computational algorithms and databases have reshaped our understanding of the often spectacular biomolecular dynamics enabled by soft linkers. Absence of such motion, as in so-called molecular rulers, also has desirable functional effects in protein architecture. We review here the historic discovery and current understanding of the nature of domains and their linkers from a structural, computational, and biophysical point of view. A number of emerging applications, based on the current understanding of the structural properties

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Sparsely populated folding intermediates of the Fyn SH3 domain: Matching native-centric essential dynamics and experiment

Cited by 32 publications

References 51 publications

Competition between native topology and nonnative interactions in simple and complex folding kinetics of natural and designed proteins

Competition between native topology and nonnative interactions in simple and complex folding kinetics of natural and designed proteins

Identification of a Conserved Aggregation-Prone Intermediate State in the Folding Pathways of Spc-SH3 Amyloidogenic Variants

Control of protein functional dynamics by peptide linkers

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