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The different coordination modes and fast ligand exchange of zinc coordination has been suggested to be one key catalytic feature of the zinc ion which makes it an invaluable metal in biological catalysis. However, partly because of the well-known difficulties for zinc to be characterized by spectroscopy methods, evidence for dynamic nature of the catalytic zinc coordination has so far mainly been indirect. In this work, Born-Oppenheimer ab initio Quantum Mechanical/Molecular Mechanical (QM/MM) molecular dynamics (MID) simulation has been employed, which allows for a first-principle description of the dynamics of the metal active site while properly including effects of the heterogeneous and fluctuating protein environment. Our simulations have provided direct evidence regarding inherent flexibility of the catalytic zinc coordination shell in thermolysin (TLN) and histone deacetylase 8 (HDAC8). We have observed different coordination modes and fast ligand exchange during the picosecond's time scale. For TLN, the coordination of the carboxylate group of Glul 66 to zinc is found to continuously change between monodentate and bidentate manner dynamically, while for HDAC8, the flexibility mainly comes from the coordination to a nonamino acid ligand. Such distinct dynamics in the zinc coordination shell between two enzymes suggests that the catalytic role of zinc in TLN and HDAC8 is likely to be different in spite of the fact that both catalyze the hydrolysis of the amide bond. Meanwhile, considering that such Born-Oppenheimer ab initio QM/MM MID simulations are very much desired but are widely considered to be too computationally expensive to be feasible, our current study demonstrates the viability and powerfulness of this state-of-the-art approach in simulating metalloenzymes.NIH [R01-GM079223]; NSF [CHE-CAREER-0448156]; China Scholarship Counci

Flexibility of Catalytic Zinc Coordination in Thermolysin and HDAC8: A Born−Oppenheimer ab Initio QM/MM Molecular Dynamics Study