Benchmarking all-atom simulations using hydrogen exchange

Skinner, John J.; Yu, Wookyung; Gichana, Elizabeth K.; Baxa, Michael C.; Hinshaw, James R.; Freed, Karl F.; Sosnick, Tobin R.

doi:10.1073/pnas.1404213111

Title: Benchmarking all-atom simulations using hydrogen exchange

Journal Article · Mon Oct 27 04:00:00 UTC 2014 · Proceedings of the National Academy of Sciences of the United States of America

DOI: https://doi.org/10.1073/pnas.1404213111 · OSTI ID:1348915

Skinner, John J. ^[1]; Yu, Wookyung ^[2]; Gichana, Elizabeth K. ^[3]; Baxa, Michael C. ^[4]; Hinshaw, James R. ^[5]; Freed, Karl F. ^[6]; Sosnick, Tobin R. ^[7]

Univ. of Chicago, IL (United States). Dept. of Biochemisry and Molecular Biology; Office of Scientific and Technical Information (OSTI)
Univ. of Chicago, IL (United States). Dept. of Biochemisry and Molecular Biology; Daegu Gyeongbuk Inst. of Science and Technology (Korea). Center for Proteome Biophysics
Univ. of Chicago, IL (United States). Dept. of Biochemisry and Molecular Biology
Univ. of Chicago, IL (United States). Dept. of Biochemisry and Molecular Biology and Inst. for Biophysical Dynamics
Univ. of Chicago, IL (United States). Dept. of Chemistry
Univ. of Chicago, IL (United States). Dept. of Chemistry and James Franck Inst. and Computation Inst.
Univ. of Chicago, IL (United States). Dept. of Biochemisry and Molecular Biology and Inst. for Biophysical Dynamics and Computation Inst.

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.

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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, Journal Name: Proceedings of the National Academy of Sciences of the United States of America Journal Issue: 45 Vol. 111; ISSN 0027-8424

Publisher:: National Academy of Sciences, Washington, DC (United States)Copyright Statement

Country of Publication:: United States

Language:: English

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