Topology of DNA G-Quadruplexes Can Be Harnessed in Holliday Junction-Based DNA Suprastructures to Control and Optimize Their Biocatalytic Properties

0574950 - BFÚ 2024 RIV US eng J - Journal Article
Qiu, D. - Cheng, M. - Stadlbauer, Petr - Chen, J. - Langer, M. - Zhang, X. - Gao, Q. - Ju, H. - Šponer, Jiří - Mergny, Jean-Louis - Monchaud, D. - Zhou, J.
Topology of DNA G-Quadruplexes Can Be Harnessed in Holliday Junction-Based DNA Suprastructures to Control and Optimize Their Biocatalytic Properties.
ACS Catalysis. Roč. 13, č. 16 (2023), s. 10722-10733. ISSN 2155-5435. E-ISSN 2155-5435
R&D Projects: GA MŠMT EF15_003/0000477; GA ČR(CZ) GA21-23718S
Institutional support: RVO:68081707
Keywords : G-quadruplex * DNAzyme * Holliday junction * molecular dynamics simulations * catalytic mechanism
OECD category: Physical chemistry
Impact factor: 12.9, year: 2022
Method of publishing: Open access
https://pubs.acs.org/doi/10.1021/acscatal.3c02818

Thenature, composition, and topology of the active sitesof bothnatural and artificial enzymes are key determinants of their catalyticperformance. While interesting structural insights have been obtainedfor natural enzymes (e.g., horseradish peroxidase, HRP), the accuratecatalytic microenvironment of HRP-mimicking DNA-based catalysts knownas G-quadruplex (GQ)/hemin DNAzymes is still unclear. Herein, we reporton a strategy allowing for fully controlling the nature of the activesite of GQ DNAzyme, precisely manipulating the composition and topologyof the hemin (Fe(III)-protoporphyrin IX) cofactor binding site. Thiswas achieved by introducing GQ within a Holliday junction (HJ) suprastructurethat enables to seize control of both the GQ folding topology (parallel,antiparallel, hybrid) and the GQ strand directionality (clockwise,counter-clockwise). By doing so, we demonstrate that the differentGQ topologies are equivalent for both hemin binding and activationand that the flanking nucleotides (dA or dTC) modulate the activationof hemin in a GQ topology-dependent manner. Our experimental findingsare supported by the most extensive molecular dynamics simulationsever been done on GQ DNAzyme, thus providing unique mechanistic insightsinto the biocatalytic activity of GQs.
Permanent Link: https://hdl.handle.net/11104/0349523