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Dynamics of water molecules in the active-site cavity of human cytochromes P450

Rydberg, Patrik LU ; Rod, Thomas LU ; Olsen, Lars and Ryde, Ulf LU (2007) In The Journal of Physical Chemistry Part B 111(19). p.5445-5457
Abstract
We have studied the dynamics of water molecules in six crystal structures of four human cytochromes P450, 2A6, 2C8, 2C9, and 3A4, with molecular dynamics simulations. In the crystal structures, only a few water molecules are seen and the reported sizes of the active-site cavity vary a lot. In the simulations, the cavities are completely filled with water molecules, although with similar to 20% lower density than in bulk water. The 2A6 protein differs from the other three in that it has a very small cavity with only two water molecules and no exchange with the surroundings. The other three proteins have quite big cavities, with 41 water molecules on average in 2C8 and 54-58 in 2C9 and 3A4, giving a water volume of 1500-2100 angstrom(3). The... (More)
We have studied the dynamics of water molecules in six crystal structures of four human cytochromes P450, 2A6, 2C8, 2C9, and 3A4, with molecular dynamics simulations. In the crystal structures, only a few water molecules are seen and the reported sizes of the active-site cavity vary a lot. In the simulations, the cavities are completely filled with water molecules, although with similar to 20% lower density than in bulk water. The 2A6 protein differs from the other three in that it has a very small cavity with only two water molecules and no exchange with the surroundings. The other three proteins have quite big cavities, with 41 water molecules on average in 2C8 and 54-58 in 2C9 and 3A4, giving a water volume of 1500-2100 angstrom(3). The two crystal structures of 2C9 differ quite appreciably, whereas those of 3A4 are quite similar. The active-site cavity is connected to the surroundings by three to six channels, through which there is a quite frequent exchange of water molecules (one molecule is exchanged every 30-200 ps), except in 2A6. Most of the channels are observed also in the crystal structures, but two to three channels in each protein open only during the simulations. There are no water molecules close to the heme iron ion in these simulations of the high-spin ferric state (the average distance to the closest water molecule is 3.3-5 angstrom), and there are few ordered water molecules in the active sites, none of which is conserved in all proteins. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
The Journal of Physical Chemistry Part B
volume
111
issue
19
pages
5445 - 5457
publisher
The American Chemical Society
external identifiers
  • wos:000246341300057
  • scopus:34249829268
ISSN
1520-5207
DOI
10.1021/jp070390c
language
English
LU publication?
yes
id
10f004a8-650a-4b20-bddb-c53dfbd18771 (old id 664519)
date added to LUP
2007-12-18 12:36:06
date last changed
2017-09-24 04:22:33
@article{10f004a8-650a-4b20-bddb-c53dfbd18771,
  abstract     = {We have studied the dynamics of water molecules in six crystal structures of four human cytochromes P450, 2A6, 2C8, 2C9, and 3A4, with molecular dynamics simulations. In the crystal structures, only a few water molecules are seen and the reported sizes of the active-site cavity vary a lot. In the simulations, the cavities are completely filled with water molecules, although with similar to 20% lower density than in bulk water. The 2A6 protein differs from the other three in that it has a very small cavity with only two water molecules and no exchange with the surroundings. The other three proteins have quite big cavities, with 41 water molecules on average in 2C8 and 54-58 in 2C9 and 3A4, giving a water volume of 1500-2100 angstrom(3). The two crystal structures of 2C9 differ quite appreciably, whereas those of 3A4 are quite similar. The active-site cavity is connected to the surroundings by three to six channels, through which there is a quite frequent exchange of water molecules (one molecule is exchanged every 30-200 ps), except in 2A6. Most of the channels are observed also in the crystal structures, but two to three channels in each protein open only during the simulations. There are no water molecules close to the heme iron ion in these simulations of the high-spin ferric state (the average distance to the closest water molecule is 3.3-5 angstrom), and there are few ordered water molecules in the active sites, none of which is conserved in all proteins.},
  author       = {Rydberg, Patrik and Rod, Thomas and Olsen, Lars and Ryde, Ulf},
  issn         = {1520-5207},
  language     = {eng},
  number       = {19},
  pages        = {5445--5457},
  publisher    = {The American Chemical Society},
  series       = {The Journal of Physical Chemistry Part B},
  title        = {Dynamics of water molecules in the active-site cavity of human cytochromes P450},
  url          = {http://dx.doi.org/10.1021/jp070390c},
  volume       = {111},
  year         = {2007},
}