Benchmarking all-atom simulations using hydrogen exchange
| Autor: | John J. Skinner, Michael C. Baxa, Wookyung Yu, Tobin R. Sosnick, Karl F. Freed, Elizabeth K. Gichana, James R. Hinshaw |
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| Rok vydání: | 2014 |
| Předmět: |
Multidisciplinary
biology Hydrogen Hydrogen bond Deuterium Exchange Measurement chemistry.chemical_element Hydrogen Bonding Biological Sciences Recombinant Proteins Protein Structure Tertiary Crystallography Molecular dynamics chemistry GTP-Binding Proteins Chemical physics Excited state Intramolecular force biology.protein Protein folding Protein G Protein Unfolding |
| Zdroj: | Proceedings of the National Academy of Sciences. 111:15975-15980 |
| ISSN: | 1091-6490 0027-8424 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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