Computational insights into the electrostatic origins of mechanistic selectivity: human topoisomerase IIα enforces ATP hydrolysis via substrate-assisted catalysis.
- 1Theory Department, National Institute of Chemistry Hajdrihova 19 1000 Ljubljana Slovenia [email protected] [email protected].
- 2Faculty of Chemistry, Jagiellonian University Gronostajowa 2 30-387 Cracow Poland.
- 3University of Ljubljana, Faculty of Pharmacy Aškerčeva 7 1000 Ljubljana Slovenia.
Abstract
Human DNA topoisomerase IIα (topo IIα) is an essential molecular motor and a premier anticancer target. While ATP hydrolysis is critical for its function, the origin of the presumed mechanistic preference of the substrate-assisted catalysis (SAC) over the other proposed general base catalysis (GBC) pathway remains an open question. By employing Density Functional Theory (DFT) combined with a point-charge electrostatic embedding approach on reaction pathways previously derived from QM/MM simulations, the enzyme's preorganized electrostatics was explicitly isolated. This analysis reveals a massive ∼40 kcal mol⁻¹ electrostatic preference for the SAC over the GBC pathway, a phenomenon termed mechanistic selectivity. Residue-wise electrostatic decomposition demonstrates that only 16 amino acids are responsible for the vast majority of this selectivity. Furthermore, coulombic interaction and Natural Bond Orbital (NBO) analyses indicate that this electrostatic network enforces selectivity by modulating the charge distribution and specific orbital occupancies of the reaction center. Ultimately, identification of amino acids that electrostatically promote the ATP hydrolysis provides mechanistic insights that may aid in the future development of next-generation catalytic inhibitors that can bypass the genotoxicity of traditional topoisomerase poisons.
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BibTeX
@article{novotny2026computational,
title = {{Computational insights into the electrostatic origins of mechanistic selectivity: human topoisomerase IIα enforces ATP hydrolysis via substrate-assisted catalysis.}},
author = {Aleš Novotný and Andrzej J Kałka and Andrej Perdih and Jernej Stare},
journal = {RSC advances},
year = {2026},
month = oct,
doi = {10.1039/d6ra05904j},
url = {https://europepmc.org/article/MED/42923626},
note = {CC BY-NC},
}
RIS
TY - JOUR
TI - Computational insights into the electrostatic origins of mechanistic selectivity: human topoisomerase IIα enforces ATP hydrolysis via substrate-assisted catalysis.
AU - Aleš Novotný
AU - Andrzej J Kałka
AU - Andrej Perdih
AU - Jernej Stare
PY - 2026
DA - 2026/10/22
JO - RSC advances
DO - 10.1039/d6ra05904j
UR - https://europepmc.org/article/MED/42923626
AB - Human DNA topoisomerase IIα (topo IIα) is an essential molecular motor and a premier anticancer target. While ATP hydrolysis is critical for its function, the origin of the presumed mechanistic preference of the substrate-assisted catalysis (SAC) over the other proposed general base catalysis (GBC) pathway remains an open question. By employing Density Functional Theory (DFT) combined with a point-charge electrostatic embedding approach on reaction pathways previously derived from QM/MM simulations, the enzyme's preorganized electrostatics was explicitly isolated. This analysis reveals a massive ∼40 kcal mol⁻¹ electrostatic preference for the SAC over the GBC pathway, a phenomenon termed mechanistic selectivity. Residue-wise electrostatic decomposition demonstrates that only 16 amino acids are responsible for the vast majority of this selectivity. Furthermore, coulombic interaction and Natural Bond Orbital (NBO) analyses indicate that this electrostatic network enforces selectivity by modulating the charge distribution and specific orbital occupancies of the reaction center. Ultimately, identification of amino acids that electrostatically promote the ATP hydrolysis provides mechanistic insights that may aid in the future development of next-generation catalytic inhibitors that can bypass the genotoxicity of traditional topoisomerase poisons.
SN - 2046-2069
ER -