Novel Zinc Protein Molecular Dynamics Simulations: Steps Toward Antiangiogenesis for Cancer Treatment
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Angiogenesis is the formation of new blood vessels induced by tumors as a lifeline for oxygen and nutrients and as exits for spread of cancer cells. Blocking tumors′ blood supply could starve tumors thus saving cancer patients, and is termed antiangiogenesis. Matrix metalloproteinases (MMPs) are a class of proteins containing Zn2+ in the active site that cleave the constituents of the extracellular matrix and control angiogenesis. Selective inhibitors of MMPs therefore hold promise in antiangiogenesis for treating cancers, but development of such inhibitors is currently hampered by a paucity of effective computational methods for evaluating the intermolecular interactions between zinc and its coordinates and for performing nanosecond length molecular dynamics simulation of zinc proteins. Here I report an approach for simulating the four-coordinate zinc complex in proteins without use of covalent bonds or harmonic restraints applied to the zinc complex. This approach uses four cationic dummy atoms tetrahedrically placed around the zinc nucleus to mimic zinc′s 4s4p3 vacant orbitals that accommodate lone-pair electrons of the zinc coordinates thus imposing the orientational requirement for the zinc coordinates and simulating zinc′s propensity to a tetrahedral coordination geometry. It hence permits evaluating binding free energy of zinc coordinates and simulating the exchanges of zinc′s ambidentate coordinates in proteins, and is expected to expedite the search of effective angiogenesis inhibitors to combat cancers.
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