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Title: Benchmarking all-atom simulations using hydrogen exchange

Abstract

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.

Authors:
 [1];  [2];  [1];  [3];  [4];  [5];  [6]
+ Show Author Affiliations
  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.
Publication Date:
Research Org.:
Univ. of Chicago, IL (United States)
Sponsoring Org.:
USDOE Office of Science (SC)
OSTI Identifier:
1348915
Grant/Contract Number:  
AC02-06CH11357
Resource Type:
Accepted Manuscript
Journal Name:
Proceedings of the National Academy of Sciences of the United States of America
Additional Journal Information:
Journal Volume: 111; Journal Issue: 45; Journal ID: ISSN 0027-8424
Publisher:
National Academy of Sciences, Washington, DC (United States)
Country of Publication:
United States
Language:
English
Subject:
74 ATOMIC AND MOLECULAR PHYSICS; molecular dynamics; unfolded state; denatured states; HX; protein folding

Citation Formats

Skinner, John J., Yu, Wookyung, Gichana, Elizabeth K., Baxa, Michael C., Hinshaw, James R., Freed, Karl F., and Sosnick, Tobin R. Benchmarking all-atom simulations using hydrogen exchange. United States: N. p., 2014. Web. doi:10.1073/pnas.1404213111.
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Skinner, John J., Yu, Wookyung, Gichana, Elizabeth K., Baxa, Michael C., Hinshaw, James R., Freed, Karl F., & Sosnick, Tobin R. Benchmarking all-atom simulations using hydrogen exchange. United States. https://doi.org/10.1073/pnas.1404213111
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Skinner, John J., Yu, Wookyung, Gichana, Elizabeth K., Baxa, Michael C., Hinshaw, James R., Freed, Karl F., and Sosnick, Tobin R. Mon . "Benchmarking all-atom simulations using hydrogen exchange". United States. https://doi.org/10.1073/pnas.1404213111. https://www.osti.gov/servlets/purl/1348915.
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@article{osti_1348915,
title = {Benchmarking all-atom simulations using hydrogen exchange},
author = {Skinner, John J. and Yu, Wookyung and Gichana, Elizabeth K. and Baxa, Michael C. and Hinshaw, James R. and Freed, Karl F. and Sosnick, Tobin R.},
abstractNote = {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.},
doi = {10.1073/pnas.1404213111},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
number = 45,
volume = 111,
place = {United States},
year = {Mon Oct 27 00:00:00 EDT 2014},
month = {Mon Oct 27 00:00:00 EDT 2014}
}
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