Tyrosyl-DNA phosphodiesterase 1 (Tdp1) is a DNA repair enzyme which removes a variety of covalent adducts from DNA through hydrolysis. The catalytic phosphoryl transfer reaction hydrolyses the phosphodiester bond between the tyrosine residue and the 3’-phosphate. The detailed reaction mechanism at atomic-level has been studied by a small quantum mechanics (QM)-cluster model using density functional theory (DFT) computations by DeYonker and Webster.<sup>1</sup> In this current study, two QM-cluster models are automatically built by the python toolkit RINRUS (Residue Interaction Network Residue Selector) ranging in size from 260 – 371 atoms and based on residue interaction of the enzyme-substrate complex. First, the nitrogen atom from the histidine residue (His263) of the enzyme covalently bonds to the phosphorus atom and forms a five-coordinate intermediate state. Next, another histidine residue (His493) donates a proton to the p-cresolate ligand (OTyr) oxygen which leads to the bond breaking between the phosphorus atom and oxygen of OTyr. In the subsequential hydrolysis step, one water molecule comes into the active site and donates its proton to His493, and the OH group performs nucleophilic attack on the phosphorus atom, leading the P-N enzyme-substrate covalent bond to break. From this study as well as many previous studies in our group,<sup>1-4</sup> RINRUS is shown to be very powerful for studying enzymatic reactions by identifying important residues in the active site for better understanding the reaction mechanism, and automating QM-cluster model building via simple, easy to learn workflows.

A QM-cluster model study the phosphoryl transfer mechanisms of Tyrosyl-DNA phosphodiesterase 1 (Tdp1)

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