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Internet Electronic Journal of Molecular Design - IEJMD, ISSN 1538-6414, CODEN IEJMAT
| ABSTRACT - Internet Electron. J. Mol. Des. May 2008, Volume 7, Number 5, 97-113 |
The Calcium Ion and Conserved Water Molecules in Neuraminidases:
Roles and Implications for Substrate Binding
Gang Yang, Zhiwei Yang, Yuangang Zu, Xiaomin Wu, and Yujie Fu
Internet Electron. J. Mol. Des. 2008, 7, 97-113
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Abstract:
Neuraminidases are essential to the replication of influenza virus by catalyzing
the cleavage of the a-ketosidic connection between the sugar residue and the
sialic acid. Our aim in this paper was to study the roles of the calcium ion and
conserved water molecules played during the substrate bindings towards the N9
subtype neuraminidase. In addition, the interaction modes between substrates and
receptors were predicted based on structural and property analyses, which were
confirmed by docking results. Molecular mechanics and molecular docking
simulations as well as density functional calculations were performed using
InsightII 2005 and Gaussian 98 software packages. With the inclusion of the
calcium ion, the neuraminidase active site is close in both size and shape to that of
the crystal structure whereas shrunk severely in the absence of the calcium ion as
confirmed by binding-site searching results. It was also found that the calcium ion
or/and conserved water molecules cause the secondary structural transitions of the
active site. As a result of structural transformations, the properties of the sub-regions
in the active site are greatly altered. The molecular docking results are in
good agreement with the above implications from structural and property
analyses. The calcium ion is crucial to the maintenance of the active site of
neuraminidase whereas the conserved water molecules exert a relatively small
influence. The binding modes between substrates and receptors can be well
predicted via structural and property analyses: sub-regions 1 and 3 (S1 and S3)
are responsible for the locations of substrates whereas the orientations of
substrates can be changed by sub-regions 2 and 4 (S2 and S4). Accordingly, the
present results are useful to guide the substrate-receptor interaction studies and
structure-based rational drug designs.
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