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PEDS Advance Access published online on April 28, 2004
Protein Engineering Design and Selection, doi:10.1093/protein/gzh033
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Received December 4, 2003
Revised March 21, 2004
Accepted March 31, 2004

Article

Cluster analysis of water molecules in alanine racemase and their putative structural role

Gabriela Mustata 1 James M. Briggs 2*

1 Department of Biology and Biochemistry, University of Houston, Houston, TX 77204-5001, USA; Current address: Emisphere Technologies, Inc., Tarrytown, NY 10591, USA
2 Department of Biology and Biochemistry, University of Houston, Houston, TX 77204-5001, USA

* To whom correspondence should be addressed. E-mail: jbriggs{at}uh.edu.


  Abstract

Conservation of water molecules was identified by a cluster analysis of seven crystal structures of alanine racemase from Bacillus stearothermophilus. A total of 47 clusters of consensus water sites were determined and found to be highly localized, as indicated by their low mobilities. These clusters are located in the region of the active sites as well as at the interface between the N-terminal domain (the {alpha} /{beta} barrel) of the first monomer and the C-terminal domain of the second monomer. The clusters located at the dimer interface form extensive hydrogen-bonding networks linked to the protein backbone. These water-mediated hydrogen-bonds, as well as all hydrogen-bonding interactions at the dimer interface, were monitored during a 2 ns molecular dynamics simulation and showed that when the inhibitor propionate was bound to the enzyme, some of these interactions were disrupted. The data we present here indicate that the consensus water sites identified at the interface between the two monomers of alanine racemase may play a structural role, which is to maintain and stabilize the alanine racemase dimer. A second role might be to continuously supply the active site with water molecules in order to allow rapid equilibration of active site protons with the solvent.

Keywords: alanine racemase/cluster analysis/molecular dynamics


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