Schematic diagram of binding mechanisms among ligands, CAT, ZnF1, ZnF3 and DSB (4OPX).

CAT area includes WGR (green cartoon), HD (red cartoon) and ART (blue cartoon). (a) Interaction between ligand and CAT. (b) Interaction between ZnF1 and CAT. (c) Interaction between ZnF3 and CAT. (d) Interaction between DSB and CAT. (e) Interaction between ZnF1 and DSB. (f) Interaction between ZnF3 and DSB. (g) Interaction between ZnF1 and ZnF3.</p

The calculated (MM/GBSA) binding free energies of ZnF1/CAT.

The calculated (MM/GBSA) binding free energies of ZnF1/CAT.</p

Contains supporting figures.

The catalytic (CAT) domain is a key region of poly (ADP-ribose) polymerase 1 (PARP1), which has crucial interactions with inhibitors, DNA, and other domains of PARP1. To facilitate the development of potential inhibitors of PARP1, it is of great significance to clarify the differences in structural dynamics and key residues between CAT/inhibitors and DNA/PARP1/inhibitors through structure-based computational design. In this paper, conformational changes in PAPR1 and differences in key residue interactions induced by inhibitors were revealed at the molecular level by comparative molecular dynamics (MD) simulations and energy decomposition. On one hand, PARP1 inhibitors indirectly change some residues of the CAT domain which interact with DNA and other domains. Furthermore, the interaction between ligands and catalytic binding sites can be transferred to the DNA recognition domain of PARP1 by a strong negative correlation movement among multi-domains of PARP1. On the other hand, it is not reliable to use the binding energy of CAT/ligand as a measure of ligand activity, because it may in some cases differs greatly from the that of PARP1/DNA/ligand. For PARP1/DNA/ligand, the stronger the binding stability between the ligand and PARP1, the stronger the binding stability between PARP1 and DNA. The findings of this work can guide further novel inhibitor design and the structural modification of PARP1 through structure-based computational design.</div

The calculated (MMGBSA) binding free energies of the ZnF1/DSB for Model 1 to Model 4.

The calculated (MMGBSA) binding free energies of the ZnF1/DSB for Model 1 to Model 4.</p

Fig 2 -

(a) Per-residue RMSFs for ZnF1 in Model 1 to Model 4. (b) The three-dimensional structure diagram of ZnF1 (4OPX). The interaction interface of ZnF1/DSB and ZnF1/CAT are represented by blue and red, respectively, and the corresponding residues are shown in blue and red. (c) Per-residue energy contribution spectra of ZnF1 on the surface of ZnF1/DSB for Model 1 to Model 4. Red, blue, green, and yellow bars represent Lig1, Lig2, Lig3, and without ligand binding to CAT (marked as WLig). (d) Per-residue energy contribution spectra of ZnF1 on the surface of ZnF1/CAT for Model 1 to Model 4. Red, blue, green, and yellow bars represent Lig1, Lig2, Lig3, and WLig.</p

The calculated (MMGBSA) binding free energies of DSB/CAT.

The calculated (MMGBSA) binding free energies of DSB/CAT.</p

Fig 1 -

(a) Three-dimensional diagram of the binding system (4OPX). ZnF1, ZnF3 and CAT (including WGR) are depicted in red, yellow, and green, respectively. DSB is depicted in blue. Ligand is shown in purple stick model. (b) Two-dimensional diagram of C10H10FNO2, marked as Lig1. (c) Two-dimensional diagram of C16H11NO5, marked as Lig2. (c) Two-dimensional diagram of C22H22N2O5, marked as Lig3.</p

The calculated (MMGBSA) binding free energies of ZnF3/DSB.

The calculated (MMGBSA) binding free energies of ZnF3/DSB.</p

Constructed models.

The catalytic (CAT) domain is a key region of poly (ADP-ribose) polymerase 1 (PARP1), which has crucial interactions with inhibitors, DNA, and other domains of PARP1. To facilitate the development of potential inhibitors of PARP1, it is of great significance to clarify the differences in structural dynamics and key residues between CAT/inhibitors and DNA/PARP1/inhibitors through structure-based computational design. In this paper, conformational changes in PAPR1 and differences in key residue interactions induced by inhibitors were revealed at the molecular level by comparative molecular dynamics (MD) simulations and energy decomposition. On one hand, PARP1 inhibitors indirectly change some residues of the CAT domain which interact with DNA and other domains. Furthermore, the interaction between ligands and catalytic binding sites can be transferred to the DNA recognition domain of PARP1 by a strong negative correlation movement among multi-domains of PARP1. On the other hand, it is not reliable to use the binding energy of CAT/ligand as a measure of ligand activity, because it may in some cases differs greatly from the that of PARP1/DNA/ligand. For PARP1/DNA/ligand, the stronger the binding stability between the ligand and PARP1, the stronger the binding stability between PARP1 and DNA. The findings of this work can guide further novel inhibitor design and the structural modification of PARP1 through structure-based computational design.</div

Fig 5 -

(a) Comparison of RMSFs for CAT between DSB/ZnF1/ZnF3/CAT/Lig1 and CAT/Lig1. (b) Comparison of RMSFs for CAT between DSB/ZnF1/ZnF3/CAT/Lig2 and CAT/Lig2. (c) Comparison of RMSFs for CAT between DSB/ZnF1/ZnF3/CAT/Lig3 and CAT/Lig3. (d-f) Per-residue energy contribution spectra of CAT on the surface of CAT/Lig1, CAT/Lig2 and CAT/Lig3, respectively. (g-i) Comparison of binding poses for these ligands between multi-domain and CAT monomers (4OPX, 4OQA and 4OQB). The complex containing the interactions between DSB, CAT, ZnF1, ZnF2 and ligands is depicted as a red stick model, and the blue one stands for the CAT and ligand complex.</p