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Benchmarking all-atom simulations using hydrogen exchange

Title
Benchmarking all-atom simulations using hydrogen exchange
Author(s)
Skinner, John J.Yu, WookyungGichana, Elizabeth K.Baxa, Michael C.Hinshaw, James R.Freed, Karl F.Sosnick, Tobin R.
Issued Date
2014-11-11
Citation
Proceedings of the National Academy of Sciences of the United States of America, v.111, no.45, pp.15975 - 15980
Type
Article
Author Keywords
molecular dynamicsunfolded statedenatured statesHXprotein folding
Keywords
MOLECULAR-DYNAMICS SIMULATIONSFAST-FOLDING PROTEINSUNFOLDED-STATEFRET SPECTROSCOPYLAMBDA-REPRESSORRIBONUCLEASE-AEXCITED-STATESBOND FORMATIONMODELSDENATURANT
ISSN
0027-8424
Abstract
Long-time molecular dynamics (MD) simulations are now able to fold small proteins reversibly to their native structures [Lindorff-Larsen K, Piana S, Dror RO, Shaw DE (2011) Science 334(6055):517-520]. These results indicate that modern force fields can reproduce the energy surface near the native structure. To test how well the force fields recapitulate the other regions of the energy surface, MD trajectories for a variant of protein G are compared with data from site-resolved hydrogen exchange (HX) and other biophysical measurements. Because HX monitors the breaking of individual H-bonds, this experimental technique identifies the stability and H-bond content of excited states, thus enabling quantitative comparison with the simulations. Contrary to experimental findings of a cooperative, all-or-none unfolding process, the simulated denatured state ensemble, on average, is highly collapsed with some transient or persistent native 2° structure. The MD trajectories of this protein G variant and other small proteins exhibit excessive intramolecular H-bonding even for the most expanded conformations, suggesting that the force fields require improvements in describing H-bonding and backbone hydration. Moreover, these comparisons provide a general protocol for validating the ability of simulations to accurately capture rare structural fluctuations.
URI
http://hdl.handle.net/20.500.11750/2637
DOI
10.1073/pnas.1404213111
Publisher
National Academy of Sciences
Related Researcher
  • 유우경 Yu, Wookyung
  • Research Interests protein biophysics; protein folding; protein dynamics and conformational change
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Department of Brain Sciences Laboratory of Protein Biophysics 1. Journal Articles

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