Φ-Analysis at the Experimental Limits: Mechanism of β-Hairpin Formation

Petrovich, Miriana; Jönsson, Anna K.; Ferguson, Neil; Daggett, Valerie; Fersht, Alan R.

doi:10.1016/j.jmb.2006.05.050

Cited by 96 publications

(205 citation statements)

References 42 publications

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“…For efficient folding, approximate turn structure is likely formed early in the folding pathway to allow for structural collapse, and several studies have characterized the importance of turns to both folding (as folding nuclei) [21][22][23] and stability. 24 We report a comprehensive u-value analysis for each of the 11 turns of FGF-1, involving a total of 44 residue positions within the 140 amino acid FGF-1 protein.…”

Section: Introductionmentioning

confidence: 99%

Experimental support for the foldability–function tradeoff hypothesis: Segregation of the folding nucleus and functional regions in fibroblast growth factor‐1

2012

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The acquisition of function is often associated with destabilizing mutations, giving rise to the stability-function tradeoff hypothesis. To test whether function is also accommodated at the expense of foldability, fibroblast growth factor-1 (FGF-1) was subjected to a comprehensive u-value analysis at each of the 11 turn regions. FGF-1, a b-trefoil fold, represents an excellent model system with which to evaluate the influence of function on foldability: because of its threefold symmetric structure, analysis of FGF-1 allows for direct comparisons between symmetryrelated regions of the protein that are associated with function to those that are not; thus, a structural basis for regions of foldability can potentially be identified. The resulting u-value distribution of FGF-1 is highly polarized, with the majority of positions described as either foldedlike or denatured-like in the folding transition state. Regions important for folding are shown to be asymmetrically distributed within the protein architecture; furthermore, regions associated with function (i.e., heparin-binding affinity and receptor-binding affinity) are localized to regions of the protein that fold after barrier crossing (late in the folding pathway). These results provide experimental support for the foldability-function tradeoff hypothesis in the evolution of FGF-1. Notably, the results identify the potential for folding redundancy in symmetric protein architecture with important implications for protein evolution and design.

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Section: Introductionmentioning

confidence: 99%

Experimental support for the foldability–function tradeoff hypothesis: Segregation of the folding nucleus and functional regions in fibroblast growth factor‐1

2012

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“…However, this artificially lowered the S-values in the turn, even in the presence of side chain interactions. Therefore, the tertiary component of the S-values better represents the amount of structure in the turn in the TS ensemble (30). The resulting S-and F-values are in good agreement for FBP28 WW domain, independent of temperature and pH (R of 0.7 between S-and F-values).…”

Section: Using Simulation To Characterize Protein Unfolding: the Ww Dmentioning

confidence: 69%

“…Fortunately, previous simulation studies have shown that protein folding is a microscopically reversible process, i.e., the unfolding pathway is essentially the same as the folding pathway both at a single temperature and comparing high temperature and quenched refolding (28,29). In addition, previous studies have shown that the unfolding process is largely insensitive to changes in temperature and that raising the temperature merely accelerates the process and the same conformational states are visited in simulations at different temperatures (16,28,30). Consequently, the use of high temperature is a reasonable choice for our high-throughput simulation effort.…”

Section: Protocols For Simulation and Analysismentioning

confidence: 99%

“…These results have been interpreted to mean that this turn is structured in the TS and acts as a structured nucleus for hairpin folding. We used MD simulations to study both the native state dynamics and the unfolding pathway of the WW domain to gain a better understanding of the role the first turn plays in hairpin formation (30,46). Multiple simulations of three WW domain proteins (FBP28, Pin1 and hYAP) were performed at 285 K and 298 K to study the native state dynamics (46).…”

Section: Using Simulation To Characterize Protein Unfolding: the Ww Dmentioning

confidence: 99%

“…Initially, simulations were run at low pH (protonation of Asp and Glu residues) at 333 K, 348 K and multiple simulations at 373 K (30,44). As part of the Dynameomics project, unfolding simulations of FBP28 WW domain (rank 194) were also run at neutral pH and 498 K. The unfolding pathway was similar across all temperatures and conditions.…”

Section: Using Simulation To Characterize Protein Unfolding: the Ww Dmentioning

confidence: 99%

See 2 more Smart Citations

Dynameomics: protein dynamics and unfolding across fold space

Jönsson

Schaeffer

Kamp

et al. 2010

BioMolecular Concepts

Self Cite

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All currently known structures of proteins together define 'protein fold space'. To increase the general understanding of protein dynamics and protein folding, we selected a set of 807 proteins and protein domains that represent 95% of the currently known autonomous folded domains present in globular proteins. Native state and unfolding simulations of these representatives are now complete and accessible via a novel database containing over 11 000 simulations. Because protein folding is a microscopically reversible process, these simulations effectively sample protein folding across all of protein fold space. Here, we give an overview of how the representative proteins were selected and how the simulations were performed and validated. We then provide examples of different types of analyses that can be performed across our large set of simulations, made possible by the database approach. We further show how the unfolding simulations can be used to compare unfolding of structural elements in isolation and in different structural contexts, using as an example a short, triple stranded b-sheet that forms the WW domain and is present in several larger unrelated proteins.

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Parallel folding pathways of Fip35 WW domain explained by infrared spectra and their computer simulation

et al. 2017

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We present a calculation of the amide I’ infrared spectra of the folded, unfolded, and intermediate states of the WW domain Fip35, a model system for β-sheet folding. Using an all-atom molecular dynamics simulation in which multiple folding and unfolding events take place we identify six conformational states and then apply perturbed matrix method quantum-mechanical calculations to determine their amide I’ infrared spectra. Our analysis focuses on two states previously identified as Fip35 folding intermediates and suggests that a three-stranded core similar to the folded state core is the main source of the spectroscopic differences between the two intermediates. In particular, we propose a hypothesis for why folding via one of these intermediates was not experimentally observed by infrared T-jump.

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Φ-Analysis at the Experimental Limits: Mechanism of β-Hairpin Formation

Cited by 96 publications

References 42 publications

Experimental support for the foldability–function tradeoff hypothesis: Segregation of the folding nucleus and functional regions in fibroblast growth factor‐1

Experimental support for the foldability–function tradeoff hypothesis: Segregation of the folding nucleus and functional regions in fibroblast growth factor‐1

Dynameomics: protein dynamics and unfolding across fold space

Parallel folding pathways of Fip35 WW domain explained by infrared spectra and their computer simulation

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