*4.1. Molecular Modeling*

The molecular model of human PARP-1 bound to DNA was constructed on the basis of the 4dqy crystal structure (chains A, B, C, M, and N) [39,40]. The coordinates of the missing loop 576–583 in the WGR domain were transferred from the 2cr9 structure. The coordinates of the loop 645–661 between the WGR and catalytic domains were predicted with the Modeller 9.20 program [41]. Next, the protein and DNA structure was optimized with AmberTools 15 and Amber 14 [42,43], according to the following protocol. Hydrogen atoms were added to the structure considering ionization of amino acid residues, and then it was solvated by 12 Å-thick layer of TIP3P water; sodium ions were added to neutralize the negative net charge. The two-stage energy minimization was then performed to relax the solvated system. At the first stage (2500 steps of the steepest descent algorithm + 2500 steps of the conjugate gradient algorithm), the DNA coordinates of the protein and DNA were kept fixed by the positional restraints of 2 kcal/(mol·Å<sup>2</sup> ) on heavy atoms. The second minimization stage (5000 steepest descent steps + 5000 conjugate gradient steps) was carried out without restraints.

To obtain the starting model of the PARP-1–DNA–7-MG complex, water molecules and ions were removed from the optimized PARP-1–DNA complex and then it was subjected to molecular docking with Lead Finder 1.1.16 [44,45]. The 7-MG molecule was docked into the active site of the PARP-1 catalytic domain using the genetic algorithm. The obtained ternary complex was re-solvated and re-optimized using the protocol described above, and subsequently studied through molecular dynamics simulation. The system was heated up from 0 to 300 K with positional restraints of 1 kcal/(mol·Å<sup>2</sup> ) on the protein, DNA, and 7-MG atoms (250 ps, constant volume) and equilibrated at 300 K (500 ps, constant pressure). Lastly, a 20 ns trajectory of equilibrium simulation was calculated and analyzed. Control data for energy minimization and MD simulation are provided in Table S1. The ff*14SB* force field [46] was used to describe the protein and DNA with molecular mechanics, and recently developed parameters [23] were used to describe the 7-MG molecule. VMD 1.9.2 was used for the visualization of structures [47].
