Mechanism of PARP1 Elongation Reaction Revealed by Molecular Modeling

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Sergey V. Pushkarev¹, Evgeny M. Kirilin^2,a, Vytas K. Švedas^1,3, Dmitry K. Nilov^3,b*

¹Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, 119234 Moscow, Russia

²Abu Dhabi, United Arab Emirates

³Belozersky Institute of Physicochemical Biology, Lomonosov Moscow State University, 119992 Moscow, Russia

^* To whom correspondence should be addressed.

Received: April 15, 2024; Revised: June 6, 2024; Accepted: June 8, 2024

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Poly(ADP-ribose) polymerase 1 (PARP1) plays a major role in the DNA damage repair and transcriptional regulation, and is targeted by a number of clinical inhibitors. Despite this, catalytic mechanism of PARP1 remains largely underexplored because of the complex substrate/product structure. Using molecular modeling and metadynamics simulations we have described in detail elongation of poly(ADP-ribose) chain in the PARP1 active site. It was shown that elongation reaction proceeds via the S_N1-like mechanism involving formation of the intermediate furanosyl oxocarbenium ion. Intriguingly, nucleophilic 2′_A-OH group of the acceptor substrate can be activated by the general base Glu988 not directly but through the proton relay system including the adjacent 3′_A-OH group.

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KEY WORDS: Poly(ADP-ribose) polymerase 1, PARP1, ADP-ribosylation, reaction mechanism, oxocarbenium ion, molecular modeling, metadynamics

DOI: 10.1134/S0006297924070046

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