Force-dependent switch in protein unfolding pathways and transition-state movements

@article{Zhuravlev2016ForcedependentSI,
  title={Force-dependent switch in protein unfolding pathways and transition-state movements},
  author={Pavel I Zhuravlev and Michael Hinczewski and Shaon Chakrabarti and Susan Marqusee and D. Thirumalai},
  journal={Proceedings of the National Academy of Sciences},
  year={2016},
  volume={113},
  pages={E715 - E724}
}
Significance Single-domain proteins with symmetrical arrangement of secondary structural elements in the native state are expected to fold by diverse pathways. However, understanding the origins of pathway diversity, and the experimental signatures for identifying it, are major challenges, especially for small proteins with no obvious symmetry in the folded states. We show rigorously that upward curvature in the logarithm of unfolding rates as a function of force (or denaturants) implies that… 

Figures and Tables from this paper

Low force unfolding of a single-domain protein by parallel pathways
TLDR
Simulations using the SOP-SC model and previous theoretical and experimental studies show that parallel unfolding of structurally unrelated single domain proteins can be determined from the dependence of log ku(f) as a function of force.
Denaturants Alter the Flux through Multiple Pathways in the Folding of PDZ Domain.
TLDR
This study demonstrates that, irrespective of the size or topology, simulations based on MTM and SOP-SC offer a theoretical framework for describing the folding of proteins, mimicking precisely the conditions used in experiments.
Denaturants alter the flux through multiple pathways in the folding of PDZ domain
TLDR
This study demonstrates that, irrespective of the size or topology, simulations based on MTM and SOP-SC offer a framework for describing the folding of proteins, mimicking precisely the conditions used in experiments.
Heterogeneity in Protein Folding and Unfolding Reactions.
TLDR
Heterogeneity in protein folding and unfolding reactions originates from the reduced cooperativity of various kinds of physicochemical interactions between various structural elements of a protein, and between a protein and solvent.
Force-Dependent Folding and Unfolding Kinetics in DNA Hairpins Reveals Transition-State Displacements along a Single Pathway.
TLDR
The results demonstrate the validity of the Leffler-Hammond postulate where the transition state approaches the folded state as force increases, implying monotonically decreasing fragility with force and a non-negative transition state susceptibility at all forces.
A small single-domain protein folds through the same pathway on- and off- the ribosome
TLDR
The results, if general, suggest the ribosome may exert a bigger influence on the folding of multi-domain proteins or protein domains that can partially fold before the entire domain sequence is outside the Ribosome exit tunnel.
Unfolding Dynamics of Ubiquitin from Constant Force MD Simulation: Entropy-Enthalpy Interplay Shapes the Free-Energy Landscape.
TLDR
The authors' simulations reveal a crossover at an intermediate force in the unfolding rate versus force curve, which can be explained in terms of an interplay between entropy and enthalpy with relative importance changing from low force to high force.
Force-dependent folding pathways in mechanically interlocked calixarene dimers via atomistic force quench simulations
Abstract Single-molecule force spectroscopy and molecular simulations are well-established techniques to study the mechanical unfolding of supramolecular complexes in various fields of biomolecular
...
...

References

SHOWING 1-10 OF 50 REFERENCES
Stretching single-domain proteins: phase diagram and kinetics of force-induced unfolding.
  • D. Klimov, D. Thirumalai
  • Biology
    Proceedings of the National Academy of Sciences of the United States of America
  • 1999
TLDR
It is shown that single-molecule force spectroscopy can be used to map the folding free energy landscape of proteins in the absence of denaturants.
Single-molecule chemo-mechanical unfolding reveals multiple transition state barriers in a small single-domain protein
TLDR
This study uses a combination of chemical denaturant, mechanical force and site-directed mutations to demonstrate the presence of multiple unfolding pathways in a simple, two-state folding protein, and shows that these multiple pathways have structurally different transition states.
Parallel protein-unfolding pathways revealed and mapped
TLDR
Changes in the flux between different transition states on parallel folding pathways are demonstrated, resulting in unprecedented upward curvature in the denaturant-dependent unfolding kinetics of a β-sandwich protein.
Direct observation of a force-induced switch in the anisotropic mechanical unfolding pathway of a protein
TLDR
It is found that this small cooperatively folded protein shows an anisotropic response to force; the protein is more mechanically resistant to force applied along a longitudinal axis compared to force applications perpendicular to the terminal β strand.
Multiple unfolding pathways of leucine binding protein (LBP) probed by single-molecule force spectroscopy (SMFS).
TLDR
The results suggest that the energy landscape of LBP is complex, with multiple intermediate states, and a large fraction of molecules go through intermediate states during the unfolding process, and unfolding through parallel pathways might be a general mechanism for the large two-domain proteins that are translocated to the bacterial periplasmic space.
Kinetic studies of the folding of heterodimeric monellin: evidence for switching between alternative parallel pathways.
Collapse kinetics and chevron plots from simulations of denaturant-dependent folding of globular proteins
TLDR
The molecular transfer model that combines measured denaturant-dependent transfer free energies for the peptide group and amino acid residues, and a coarse-grained Cα-side chain model for polypeptide chains is used to simulate the folding of src SH3 domain and lays the foundation for incorporatingDenaturant effects in a physically transparent manner either in all-atom or coarse- grained simulations.
Kinetics of protein folding: Nucleation mechanism, time scales, and pathways
The kinetics and thermodynamics of protein folding is investigated using low friction Langevin simulation of minimal continuum mode of proteins. We show that the model protein has two characteristic
Funnels, pathways, and the energy landscape of protein folding: A synthesis
TLDR
The work unifies several previously proposed ideas concerning the mechanism protein folding and delimits the regions of validity of these ideas under different thermodynamic conditions.
...
...