How Fast-Folding Proteins Fold

@article{LindorffLarsen2011HowFP,
  title={How Fast-Folding Proteins Fold},
  author={Kresten Lindorff-Larsen and Stefano Piana and Ron O. Dror and David E. Shaw},
  journal={Science},
  year={2011},
  volume={334},
  pages={517 - 520}
}
Millisecond-scale molecular dynamics simulations of 12 proteins reveal a set of common principles for protein folding. An outstanding challenge in the field of molecular biology has been to understand the process by which proteins fold into their characteristic three-dimensional structures. Here, we report the results of atomic-level molecular dynamics simulations, over periods ranging between 100 μs and 1 ms, that reveal a set of common principles underlying the folding of 12 structurally… 
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References

SHOWING 1-10 OF 64 REFERENCES
Atomic-Level Characterization of the Structural Dynamics of Proteins
TLDR
Simulation of the folding of a WW domain showed a well-defined folding pathway and simulation of the dynamics of bovine pancreatic trypsin inhibitor showed interconversion between distinct conformational states.
Protein folding and the organization of the protein topology universe.
Protein folding and misfolding: mechanism and principles
TLDR
This paper summarizes the experimental basis for these three determining principles and their consequences and indicates that cooperative native-like foldon units and the sequential stabilization process together generate predetermined stepwise pathways.
Computational design and experimental testing of the fastest-folding β-sheet protein.
Ultrafast folding of α3D: A de novo designed three-helix bundle protein
TLDR
The folding/unfolding kinetics of α3D, a small designed three-helix bundle, are described, revealing a single-exponential process consistent with a minimal folding time and indicating that a protein can fold on the 1- to 5-μs time scale.
The folding mechanism of BBL: Plasticity of transition-state structure observed within an ultrafast folding protein family.
How robust are protein folding simulations with respect to force field parameterization?
Sub-microsecond protein folding.
Optimization of rates of protein folding: the nucleation-condensation mechanism and its implications.
  • A. Fersht
  • Biology
    Proceedings of the National Academy of Sciences of the United States of America
  • 1995
TLDR
The nucleation-condensation mechanism of CI2 fulfills the criteria for fast folding, and stable intermediates do form in the folding of more complex proteins, and this may be an unavoidable consequence of increasing size and nucleation at more than one site.
Small proteins fold through transition states with native-like topologies.
...
1
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4
5
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