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A dry ligand-binding cavity in a solvated protein

Qvist, Johan LU ; Davidovic, Monika LU ; Hamelberg, Donald and Halle, Bertil LU (2008) In Proceedings of the National Academy of Sciences 105(17). p.6296-6301
Abstract
Ligands usually bind to proteins by displacing water from the binding site. The affinity and kinetics of binding therefore depend on the hydration characteristics of the site. Here, we show that the extreme case of a completely dehydrated free binding site is realized for the large nonpolar binding cavity in bovine beta-lactoglobulin. Because spatially delocalized water molecules may escape detection by x-ray diffraction, we use water (17)O and (2)H magnetic relaxation dispersion (MRD), (13)C NMR spectroscopy, molecular dynamics simulations, and free energy calculations to establish the absence of water from the binding cavity. Whereas carbon nanotubes of the same diameter are filled by a hydrogen-bonded water chain, the MRD data show that... (More)
Ligands usually bind to proteins by displacing water from the binding site. The affinity and kinetics of binding therefore depend on the hydration characteristics of the site. Here, we show that the extreme case of a completely dehydrated free binding site is realized for the large nonpolar binding cavity in bovine beta-lactoglobulin. Because spatially delocalized water molecules may escape detection by x-ray diffraction, we use water (17)O and (2)H magnetic relaxation dispersion (MRD), (13)C NMR spectroscopy, molecular dynamics simulations, and free energy calculations to establish the absence of water from the binding cavity. Whereas carbon nanotubes of the same diameter are filled by a hydrogen-bonded water chain, the MRD data show that the binding pore in the apo protein is either empty or contains water molecules with subnanosecond residence times. However, the latter possibility is ruled out by the computed hydration free energies, so we conclude that the 315 A(3) binding pore is completely empty. The apo protein is thus poised for efficient binding of fatty acids and other nonpolar ligands. The qualitatively different hydration of the beta-lactoglobulin pore and carbon nanotubes is caused by subtle differences in water-wall interactions and water entropy. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
magnetic relaxation dispersion, hydrophobic hydration, β-lactoglobulin, free energy simulation
in
Proceedings of the National Academy of Sciences
volume
105
issue
17
pages
6296 - 6301
publisher
National Acad Sciences
external identifiers
  • wos:000255534100017
  • scopus:44049083019
ISSN
1091-6490
DOI
10.1073/pnas.0709844105
language
English
LU publication?
yes
id
150831bc-2a9b-439e-b581-2010639f0d92 (old id 1227837)
date added to LUP
2008-09-05 11:06:57
date last changed
2017-10-01 03:47:36
@article{150831bc-2a9b-439e-b581-2010639f0d92,
  abstract     = {Ligands usually bind to proteins by displacing water from the binding site. The affinity and kinetics of binding therefore depend on the hydration characteristics of the site. Here, we show that the extreme case of a completely dehydrated free binding site is realized for the large nonpolar binding cavity in bovine beta-lactoglobulin. Because spatially delocalized water molecules may escape detection by x-ray diffraction, we use water (17)O and (2)H magnetic relaxation dispersion (MRD), (13)C NMR spectroscopy, molecular dynamics simulations, and free energy calculations to establish the absence of water from the binding cavity. Whereas carbon nanotubes of the same diameter are filled by a hydrogen-bonded water chain, the MRD data show that the binding pore in the apo protein is either empty or contains water molecules with subnanosecond residence times. However, the latter possibility is ruled out by the computed hydration free energies, so we conclude that the 315 A(3) binding pore is completely empty. The apo protein is thus poised for efficient binding of fatty acids and other nonpolar ligands. The qualitatively different hydration of the beta-lactoglobulin pore and carbon nanotubes is caused by subtle differences in water-wall interactions and water entropy.},
  author       = {Qvist, Johan and Davidovic, Monika and Hamelberg, Donald and Halle, Bertil},
  issn         = {1091-6490},
  keyword      = {magnetic relaxation dispersion,hydrophobic hydration,β-lactoglobulin,free energy simulation},
  language     = {eng},
  number       = {17},
  pages        = {6296--6301},
  publisher    = {National Acad Sciences},
  series       = {Proceedings of the National Academy of Sciences},
  title        = {A dry ligand-binding cavity in a solvated protein},
  url          = {http://dx.doi.org/10.1073/pnas.0709844105},
  volume       = {105},
  year         = {2008},
}