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Benchmarking all-atom simulations using hydrogen exchange
- Benchmarking all-atom simulations using hydrogen exchange
- Skinner, JJ[Skinner, John J.]; Yu, W[Yu, Wookyung]; Gichana, EK[Gichana, Elizabeth K.]; Baxa, MC[Baxa, Michael C.]; Hinshaw, JR[Hinshaw, James R.]; Freed, KF[Freed, Karl F.]; Sosnick, TR[Sosnick, Tobin R.]
- DGIST Authors
- Yu, W[Yu, Wookyung]
- Issue Date
- Proceedings of the National Academy of Sciences of the United States of America, 111(45), 15975-15980
- Article Type
- Atomic Particle; Chemistry; Denatured States; Deuterium Exchange Measurement; Deuterium Hydrogen Exchange; GTP-Binding Proteins; Guanine Nucleotide Binding Protein; HX; Hydrogen; Hydrogen Bond; Hydrogen Bonding; Hydrogen Exchange; Molecular Dynamics; Molecular Interaction; Nuclear Magnetic Resonance; Protein; Protein Denaturation; Protein Folding; Protein Structure, Tertiary; Protein Tertiary Structure; Protein Unfolding; Quality Control; Recombinant Protein; Recombinant Proteins; Unfolded State
- 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.
- National Academy of Sciences
- Related Researcher
Yu, Woo Kyung
Laboratory of Protein Biophysics
protein biophysics; protein folding; protein dynamics and conformational change
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