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

D. K. Nilov1#, S. V. Pushkarev2#, I. V. Gushchina2, G. A. Manasaryan3, K. I. Kirsanov4, and V. K. Švedas1,2,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 SN1-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