Quantum Chemical Study on the Coordination Environment of the Catalytic Zinc Ion in Matrix Metalloproteinases

X-ray analyses of matrix metalloproteinases (MMPs) have shown that the catalytic zinc ion (Zn1) can bind
to one to three water molecules in addition to three conserved histidine residues. To estimate the relative
stability of the possible Zn1 coordination structures in the active site of the MMPs, we carry out computational
analyses on the coordination environment of the Zn1 ion in the gelatinase A enzyme (or matrix
metalloproteinase 2; MMP-2). Four-, five-, and six-coordinated complexes representative of the Zn1 site are
fully characterized by means of quantum mechanical (QM) methodologies. On one hand, B3LYP/LACVP*
minimizations of various cluster models of the MMP-2 active site show that the trigonal bipyramidal geometry
is energetically favored in the gas phase and that continuum solvent effects stabilize preferentially the tetrahedral
complexes. On the other hand, B3LYP/OPLS-AA hybrid QM/molecular mechanical calculations in the solvated
catalytic domain of the MMP-2 enzyme complemented with electrostatic Poisson−Boltzmann calculations
show that the mature enzyme presents most likely a Zn1 ion coordinated by three histidine residues and two
water molecules, while the active site glutamic acid is negatively charged. In consonance with X-ray diffraction
data, other possible Zn1 configurations, a six-coordinated structure with Zn1−water as well as four- and
five-coordinated complexes with a Zn1-bound hydroxide, are predicted to be very close in energy.