Modeling of the Enzyme–Substrate Complexes of Human Poly(ADP-Ribose) Polymerase 1

---

D. K. Nilov^1#, S. V. Pushkarev^2#, I. V. Gushchina², G. A. Manasaryan³, K. I. Kirsanov⁴, and V. K. Švedas^1,2,a*

¹Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119991 Moscow, Russia

²Lomonosov Moscow State University, Faculty of Bioengineering and Bioinformatics, 119991 Moscow, Russia

³Lomonosov Moscow State University, Faculty of Fundamental Medicine, 119991 Moscow, Russia

⁴Blokhin National Medical Research Center of Oncology, Institute of Carcinogenesis, 115478 Moscow, Russia

^# These authors contributed equally to this paper.

^* To whom correspondence should be addressed.

Received August 19, 2019; Revised October 16, 2019; Accepted October 16, 2019

---

Poly(ADP-ribose) polymerase 1 (PARP-1) is a key DNA repair enzyme and an important target in cancer treatment. Conventional methods of studying the reaction mechanism of PARP-1 have limitations because of the complex structure of PARP-1 substrates; however, the necessary data can be obtained by molecular modeling. In this work, a molecular dynamics model for the PARP-1 enzyme–substrate complex containing NAD⁺ molecule and the end of the poly(ADP-ribose) chain in the form of ADP molecule was obtained for the first time. Interactions with the active site residues have been characterized where Gly863, Lys903, Glu988 play a crucial role, and the S_N1-like mechanism for the enzymatic ADP-ribosylation reaction has been proposed. Models of PARP-1 complexes with more sophisticated two-unit fragments of the growing polymer chain as well as competitive inhibitors 3-aminobenzamide and 7-methylguanine have been obtained by molecular docking.

---

KEY WORDS: DNA repair, molecular dynamics, docking, substrates, inhibitors

DOI: 10.1134/S0006297920010095

---