Web Release Date: February 25,
Dynamical Flexibility and Proton Transfer in the Arginase Active Site Probed by ab Initio Molecular Dynamics
Contribution from the Center for Molecular Modeling and Department of Chemistry, University of Pennsylvania, 231 South 34th Street, Philadelphia, Pennsylvania 19104-6323
Received October 16, 2004
Abstract:
We have used ab initio molecular dynamics (AIMD) to investigate the dynamical flexibility of the
bridged binuclear structural motif in the active site of arginase. Dynamical transformations play a crucial
role in catalysis. We have provided direct insight into the motions of the first-shell ligands with emphasis
on the chelating and bridging carboxylates. In the case of the terminal Asp234 residue we observe changes
in the binding mode (carboxylate shifts). AIMD dynamics of sufficient duration has allowed us to observe
proton transfer from the bridging nucleophile to the catalytically essential Asp 128 residue and to map the
underlying free energy surface in terms of simple reaction coordinates, such as the oxygen-oxygen distance
Ro-o and the asymmetric stretch 
. This has provided valuable insight into the nature of the last step of the
catalytic cycle. In addition, constrained molecular dynamics permitted us to compare the deprotonation
free energy of the bridging nucleophile in the case of native versus metal-depleted arginase.
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