Conformational Dynamics of the Trp-Cage Miniprotein at Its Folding Temperature

Hałabis, Anna; Żmudzińska, Wioletta; Liwo, Adam; Ołdziej, Stanisław

doi:10.1021/jp212630y

Cited by 54 publications

(84 citation statements)

References 47 publications

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“…This structural element has been a subject of discussion in MD simulations, 2,28,32 and experimental evidence for residual flexibility at this site has been reported based on both NMR structure ensembles 8,14,19,33 and crystal structures. 23 Gai and co-workers 7 have observed a more rapid phase (ca.…”

Section: Discussionmentioning

confidence: 99%

“…While there are unanswered questions concerning the Trp-cage folding pathway, with a number of groups having reported data suggesting that Trp-cage folding is not a two-state system, 19,28,33−35 these data are largely associated with structure melting analysis rather dynamics measurements. Both T-jump and NMR relaxation experiments are consistent with a net two-state process, with fewer exceptions.…”

Section: Discussionmentioning

confidence: 99%

“…4,8,14 Long-range W6/P12 and W6/R16 contacts have been identified 17 in the unfolded state of TC5b. In another study, 19 it was noted that W6/R16 NOEs are retained at and slightly above the T m to a greater extent than other long-range contacts.…”

mentioning

confidence: 91%

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Folding Dynamics and Pathways of the Trp-Cage Miniproteins

et al. 2014

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Using alternate measures of fold stability for a wide variety of Trp-cage mutants has raised the possibility that prior dynamics T-jump measures may not be reporting on complete cage formation for some species. NMR relaxation studies using probes that only achieve large chemical shift difference from unfolded values on complete cage formation indicate slower folding in some but not all cases. Fourteen species have been examined, with cage formation time constants (1/kF) ranging from 0.9–7.5 μs at 300 K. The present study does not change the status of the Trp-cage as a fast folding, essentially two-state system, although it does alter the stage at which this description applies. A diversity of prestructuring events, depending on the specific analogue examined, may appear in the folding scenario, but in all cases, formation of the N-terminal helix is complete either at or before the cage-formation transition state. In contrast, the fold-stabilizing H-bonding interactions of the buried Ser14 side chain and the Arg/Asp salt bridge are post-transition state features on the folding pathway. The study has also found instances in which a [P12W] mutation is fold destabilizing but still serves to accelerate the folding process.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Folding Dynamics and Pathways of the Trp-Cage Miniproteins

et al. 2014

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“…For Trp-Cage, some alternatively folded conformations have even lower enthalpy than the native structure (Figure 1b). In the presence of such conformations, 68 therefore, the conformational space would not be described by a simple two-state model with a folded conformation and an unfolded state of disordered conformations. Cage is not a two-state folder.…”

Section: Discussionmentioning

confidence: 99%

“…68,72 Here we carried out simulations at three different temperatures (270 K, 280 K, and 290 K) for this protein.…”

mentioning

confidence: 99%

Thermodynamics of Protein Folding Studied by Umbrella Sampling along a Reaction Coordinate of Native Contacts

Meshkin

Zhu

2017

J. Chem. Theory Comput.

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Spontaneous transitions between the native and non-native protein conformations are normally rare events that hardly take place in typical unbiased molecular dynamics simulations. It was recently demonstrated that such transitions can be well described by a reaction coordinate, Q, that represents the collective fraction of the native contacts between the protein atoms. Here we attempt to use this reaction coordinate to enhance the conformational sampling. We perform umbrella sampling simulations with biasing potentials on Q for two model proteins, Trp-Cage and BBA, using the CHARMM force field. Hamiltonian replica exchange is implemented in these simulations to further facilitate the sampling. The simulations appear to have reached satisfactory convergence, resulting in unbiased free energies as a function of Q. In addition to the native structure, multiple folded conformations are identified in the reconstructed equilibrium ensemble. Some conformations without any native contacts nonetheless have rather compact geometries and are stabilized by hydrogen bonds not present in the native

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Temperature–pressure shuffling outlier flooding method enhances the conformational sampling of proteins

et al. 2019

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Outlier flooding method (OFLOOD) is an efficient conformational sampling method developed by the authors. In the present study, to further enhance the conformational sampling efficiency, a set of parameters (temperatures and pressures) specified as inputs in the original OFLOOD were shuffled before restarting the short‐time molecular dynamics (MD) simulations. Because of the diversity of these parameters, it was confirmed that the extended OFLOOD becomes superior to the original one in finding the folding pathways of Trp‐cage. © 2019 Wiley Periodicals, Inc.

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Conformational Dynamics of the Trp-Cage Miniprotein at Its Folding Temperature

Cited by 54 publications

References 47 publications

Folding Dynamics and Pathways of the Trp-Cage Miniproteins

Folding Dynamics and Pathways of the Trp-Cage Miniproteins

Thermodynamics of Protein Folding Studied by Umbrella Sampling along a Reaction Coordinate of Native Contacts

Temperature–pressure shuffling outlier flooding method enhances the conformational sampling of proteins

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