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Title: Benchmarking all-atom simulations using hydrogen exchange

Journal Article · · Proceedings of the National Academy of Sciences of the United States of America
 [1];  [2];  [1];  [3];  [4];  [5];  [6]
  1. Univ. of Chicago, IL (United States). Dept. of Biochemisry and Molecular Biology
  2. Univ. of Chicago, IL (United States). Dept. of Biochemisry and Molecular Biology; Daegu Gyeongbuk Inst. of Science and Technology (Korea). Center for Proteome Biophysics
  3. Univ. of Chicago, IL (United States). Dept. of Biochemisry and Molecular Biology and Inst. for Biophysical Dynamics
  4. Univ. of Chicago, IL (United States). Dept. of Chemistry
  5. Univ. of Chicago, IL (United States). Dept. of Chemistry and James Franck Inst. and Computation Inst.
  6. Univ. of Chicago, IL (United States). Dept. of Biochemisry and Molecular Biology and Inst. for Biophysical Dynamics and Computation Inst.
+ Show Author Affiliations

We 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] using long-time molecular dynamics (MD) simulations. Our results indicate that modern force fields can reproduce the energy surface near the native structure. In this paper, 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. Finally and moreover, these comparisons provide a general protocol for validating the ability of simulations to accurately capture rare structural fluctuations.

Research Organization:
Univ. of Chicago, IL (United States)
Sponsoring Organization:
USDOE Office of Science (SC)
Grant/Contract Number:
AC02-06CH11357
OSTI ID:
1348915
Journal Information:
Proceedings of the National Academy of Sciences of the United States of America, Vol. 111, Issue 45; ISSN 0027-8424
Publisher:
National Academy of Sciences, Washington, DC (United States)Copyright Statement
Country of Publication:
United States
Language:
English
Citation Metrics:
Cited by: 62 works
Citation information provided by
Web of Science

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Cited By (14)

Trajectory-based training enables protein simulations with accurate folding and Boltzmann ensembles in cpu-hours journal December 2018
Using Small-Angle Scattering Data and Parametric Machine Learning to Optimize Force Field Parameters for Intrinsically Disordered Proteins journal August 2019
Commonly used FRET fluorophores promote collapse of an otherwise disordered protein journal April 2019
Studies on Molecular Dynamics of Intrinsically Disordered Proteins and Their Fuzzy Complexes: A Mini-Review journal January 2019
Molecular recognition and packing frustration in a helical protein journal December 2017
Integrating hydrogen–deuterium exchange mass spectrometry with molecular dynamics simulations to probe lipid-modulated conformational changes in membrane proteins journal October 2019
Native Contact Density and Nonnative Hydrophobic Effects in the Folding of Bacterial Immunity Proteins journal May 2015
Response to Comment on “Innovative scattering analysis shows that hydrophobic disordered proteins are expanded in water” journal August 2018
Accurately modeling nanosecond protein dynamics requires at least microseconds of simulation journal June 2015
New tricks for old dogs: improving the accuracy of biomolecular force fields by pair-specific corrections to non-bonded interactions journal January 2018
Conformational Heterogeneity and FRET Data Interpretation for Dimensions of Unfolded Proteins text January 2017
Evidence for the principle of minimal frustration in the evolution of protein folding landscapes journal February 2017
Protein dynamics revealed by hydrogen/deuterium exchange mass spectrometry: Correlation between experiments and simulation journal April 2019
A protein interaction free energy model based on amino acid residue contributions: Assessment of point mutation stability of T4 lysozyme journal March 2019

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74 ATOMIC AND MOLECULAR PHYSICS
molecular dynamics
unfolded state
denatured states
HX
protein folding