Transient Access to the Protein Interior: Simulation versus NMR.
(2013) In Journal of the American Chemical Society 135(23). p.8735-8748- Abstract
- Many proteins rely on rare structural fluctuations for their function, whereby solvent and other small molecules gain transient access to internal cavities. In magnetic relaxation dispersion (MRD) experiments, water molecules buried in such cavities are used as intrinsic probes of the intermittent protein motions that govern their exchange with external solvent. While this has allowed a detailed characterization of exchange kinetics for several proteins, little is known about the exchange mechanism. Here, we use a millisecond all-atom MD trajectory produced by Shaw et al. (Science2010, 330, 341) to characterize water exchange from the four internal hydration sites in the protein bovine pancreatic trypsin inhibitor. Using a recently... (More)
- Many proteins rely on rare structural fluctuations for their function, whereby solvent and other small molecules gain transient access to internal cavities. In magnetic relaxation dispersion (MRD) experiments, water molecules buried in such cavities are used as intrinsic probes of the intermittent protein motions that govern their exchange with external solvent. While this has allowed a detailed characterization of exchange kinetics for several proteins, little is known about the exchange mechanism. Here, we use a millisecond all-atom MD trajectory produced by Shaw et al. (Science2010, 330, 341) to characterize water exchange from the four internal hydration sites in the protein bovine pancreatic trypsin inhibitor. Using a recently developed stochastic point process approach, we compute the survival correlation function probed by MRD experiments as well as other quantities designed to validate the exchange-mediated orientational randomization (EMOR) model used to interpret the MRD data. The EMOR model is found to be quantitatively accurate, and the simulation reproduces the experimental mean survival times for all four sites with activation energy discrepancies in the range 0-3 kBT. On the other hand, the simulated hydration sites are somewhat too flexible, and the water flip barrier is underestimated by up to 6 kBT. The simulation reveals that water molecules gain access to the internal sites by a transient aqueduct mechanism, migrating as single-file water chains through transient (<5 ns) tunnels or pores. The present study illustrates the power of state-of-the-art molecular dynamics simulations in validating and extending experimental results. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/3804414
- author
- Persson, Filip LU and Halle, Bertil LU
- organization
- publishing date
- 2013
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Journal of the American Chemical Society
- volume
- 135
- issue
- 23
- pages
- 8735 - 8748
- publisher
- The American Chemical Society (ACS)
- external identifiers
-
- wos:000320483900045
- pmid:23675835
- scopus:84878943828
- pmid:23675835
- ISSN
- 1520-5126
- DOI
- 10.1021/ja403405d
- language
- English
- LU publication?
- yes
- id
- f05d30a0-3a63-48ba-8508-06cc6cf1a837 (old id 3804414)
- date added to LUP
- 2016-04-01 10:24:41
- date last changed
- 2022-01-25 22:58:07
@article{f05d30a0-3a63-48ba-8508-06cc6cf1a837,
abstract = {{Many proteins rely on rare structural fluctuations for their function, whereby solvent and other small molecules gain transient access to internal cavities. In magnetic relaxation dispersion (MRD) experiments, water molecules buried in such cavities are used as intrinsic probes of the intermittent protein motions that govern their exchange with external solvent. While this has allowed a detailed characterization of exchange kinetics for several proteins, little is known about the exchange mechanism. Here, we use a millisecond all-atom MD trajectory produced by Shaw et al. (Science2010, 330, 341) to characterize water exchange from the four internal hydration sites in the protein bovine pancreatic trypsin inhibitor. Using a recently developed stochastic point process approach, we compute the survival correlation function probed by MRD experiments as well as other quantities designed to validate the exchange-mediated orientational randomization (EMOR) model used to interpret the MRD data. The EMOR model is found to be quantitatively accurate, and the simulation reproduces the experimental mean survival times for all four sites with activation energy discrepancies in the range 0-3 kBT. On the other hand, the simulated hydration sites are somewhat too flexible, and the water flip barrier is underestimated by up to 6 kBT. The simulation reveals that water molecules gain access to the internal sites by a transient aqueduct mechanism, migrating as single-file water chains through transient (<5 ns) tunnels or pores. The present study illustrates the power of state-of-the-art molecular dynamics simulations in validating and extending experimental results.}},
author = {{Persson, Filip and Halle, Bertil}},
issn = {{1520-5126}},
language = {{eng}},
number = {{23}},
pages = {{8735--8748}},
publisher = {{The American Chemical Society (ACS)}},
series = {{Journal of the American Chemical Society}},
title = {{Transient Access to the Protein Interior: Simulation versus NMR.}},
url = {{http://dx.doi.org/10.1021/ja403405d}},
doi = {{10.1021/ja403405d}},
volume = {{135}},
year = {{2013}},
}