Abstract
Matrix metalloproteinase (MMP) is a class of metalloenzyme that cleaves peptide bonds in extracellular matrices. Their functions are important in both health and disease of animals. Here using quantum mechanics simulations of the MMP8 protein, the coordination chemistry of different metal cofactors is examined. Structural comparisons reveal that Jhan-Teller effects induced by Cu(II) coordination distorts the wild-type MMP8 active site corresponding to a significant reduction in activity observed in previous experiments. In addition, further analysis suggests that a histidine to glutamine mutation at residue number 197 can potentially allow the MMP8 protein to utilize Cu(II) in reactions. Simulations also demonstrates the requirement of a conformational change in the ligand before enzymatic cleavage. The insights provided here will assist future protein engineering efforts utilizing the MMP8 protein.
Highlights
Matrix metalloproteinase (MMP) is a class of proteins whose native functions involves the processing of extracellular matrix and cytokines [1,2]
Structural modeling was carried out starting from the Zn(II) catalytic site for MMP8 in crystal structure [19] and the position of the water molecule was modeled in before geometry optimization based on the previous structures and structural models [20, 25]
Initial guesses of these calculations were all modeled based on the MMP8 crystal structure containing the Zn(II) cofactor (Fig 2)
Summary
Matrix metalloproteinase (MMP) is a class of proteins whose native functions involves the processing of extracellular matrix and cytokines [1,2]. As a result they are essential for the signal transduction pathway in immune cells signaling. MMPs have been used in anti-cancer clinical trials[3], their functions and involvements in cancer has not been fully understood. The aim of this work is to use computational methods to provide insights into the metal selectivity of the MMPs to assist future efforts to engineer MMPs that may serve therapeutic functions
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