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Structure of the First-Shell Active Site in Metallolactamase: Effect of Water Ligands



Morris Krauss, H S. Gilson, N. Gresh


Metallolactamase active site structures are examined theoretically for clues to the differences in the enzyme active site observed in different organisms. We will show that the inherent behavior of this type of active site yields a relatively flat effective potential between the metal cations that leaves the metal-metal effective bond susceptible to perturbations from environmental interactions or by protonating the active site. In this study we have examined the behavior of the first-shell active site as a function of water bound both as a zinc ligand and hydrogen-bonded to ligands in the active site. Although the crystal structure of the active site of the zinc lactamase from B. fragilis is the initial starting point for the structure optimizations, structures very different from the equilibrium crystal structure are also obtained as well as details of the water hydrogen- bonding pattern in the active site. Structures with metal-metal bond distances exceeding 4 are calculated with each metal cation now the center of a separate complex where the two complexes are coupled by ionic hydrogen bonds. These structures are energetically comparable to the equilibrium or crystal structure. In addition, a new class of doubly bridged structures results with the cysteine and the hydroxide shared by both zinc cations. This class is relatively low in energy and includes hydrogen bonding between the aspartate carboxylate to the ligated water or hydrogen bonding to the bridging hydroxide. Protonating the active site also yields a metal-metal distance either comparable to the crystal structure or exceeding 4 depending on the site of protonation at the bridging hydroxide or the carboxylate of the Asp 103 ligand and whether the metal is zinc or cadmium. We suggest that the structures that differ from the crystal structure can play a role in the reaction or in the initial stages of metal binding as indicated by the UV-visible spectrum observed in the cobalt substituted enzyme. Metal substitution of zinc by cadmium is also examined for the different arrangements of water binding. The lowest energy structure for the Zn-Cd system is predicted to have the zinc bound at the site with three histidine ligands in agreement with a recent experimental deduction
Journal of Physical Chemistry B
No. 33


effective core potentials, enzyme active site, metal substitution, protonate active site, water hydrogen-bonding, zinc lactamase


Krauss, M. , Gilson, H. and Gresh, N. (2001), Structure of the First-Shell Active Site in Metallolactamase: Effect of Water Ligands, Journal of Physical Chemistry B (Accessed June 18, 2024)


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Created August 1, 2001, Updated February 19, 2017