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Cluster-model DFT Computational Study (Paper 2)


Human histidine triad nucleotide-binding protein 1 (hHint1) acts as a hydrolase, breaking down substrates linked to phosphoramidites. To better understand the mechanism of hHint1-catalyzed phosphoramidite hydrolysis, DFT computational studies on a 228-atom cluster model of the enzyme were performed. The following steps comprise the overall proposed mechanism: (a) proton transfer from protonated His114 to form a protonated methyl amino group (2); (b) a protonated Penta-coordinated methyl phosphorodiamidate intermediate (3) formed by nitrogen attack of His112 on the phosphorus of the methyl phosphoramidite substrate via an associative intermediate; and (c) amine (RNH2) dissociation and formation of (e) an interchange associative transition state creates a temporary tetra-coordinate phosphoryl intermediate (e) an interchange associative transition state generates a temporary tetra-coordinate phosphoryl intermediate (6); (f) the formation of a hydrolyzed nucleotide (7) that then transfers a proton back to His 114; (d) the nucleophilic attack of water on the phosphorylated histidine intermediate (5); and (g) the formation of a hydrolyzed nucleotide (7) that then transfers (9). The intermediate was stabilized and anchored in the protein active site by a water molecule acting as a proton relay. The fully associative step that results in the formation of the Penta-coordinated phosphoryl intermediate (3) was found to be the rate-limiting step, with a free energy of activation of 21.7 kcal mol1 (TS-2-3). The overall hydrolysis was beneficial by 16.1 kcal mol.

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