Enabling Programmable Dynamic DNA Chemistry Using Small-molecule DNA Binders

Overview

Journal Nat Commun

Specialty Biology

Date 2023 Jul 17

PMID 37460620

Authors

Junpeng Xu

Guan Alex Wang

Lu Gao

Lang Wu

Qian Lei

Hui Deng

Feng Li

Affiliations

Soon will be listed here.

Abstract

The binding of small molecules to the double helical structure of DNA, through either intercalation or minor groove binding, may significantly alter the stability and functionality of DNA, which is a fundamental basis for many therapeutic and sensing applications. Here, we report that small-molecule DNA binders can also be used to program reaction pathways of a dynamic DNA reaction, where DNA strand displacement can be tuned quantitatively according to the affinity, charge, and concentrations of a given DNA binder. The binder-induced nucleic acid strand displacement (BIND) thus enables innovative technologies to accelerate the discovery and characterization of bioactive small molecules. Specifically, we demonstrate the comprehensive characterization of existing and newly discovered DNA binders, where critical parameters for binding affinity and sequence selectivity can be obtained in a single, unbiased molecular platform without the need for any specialized equipment. We also engineer a tandem BIND system as a high-throughput screening assay for discovering DNA binders, through which 8 DNA binders were successfully discovered from a library of 700 compounds.

Citing Articles

Current Understanding and Translational Prospects of Tetrahedral Framework Nucleic Acids.

Gu J, Liang J, Tian T, Lin Y JACS Au. 2025; 5(2):486-520.

PMID: 40017737 PMC: 11862954. DOI: 10.1021/jacsau.4c01170.

Engineering stimuli-responsive CRISPR-Cas systems for versatile biosensing.

Cao L, Chen W, Kang W, Lei C, Nie Z Anal Bioanal Chem. 2024; .

PMID: 39601843 DOI: 10.1007/s00216-024-05678-y.

Niacinamide Antimicrobial Efficacy and Its Mode of Action via Microbial Cell Cycle Arrest.

Ziklo N, Bibi M, Sinai L, Salama P Microorganisms. 2024; 12(8).

PMID: 39203423 PMC: 11356291. DOI: 10.3390/microorganisms12081581.

Self-assembly of stabilized droplets from liquid-liquid phase separation for higher-order structures and functions.

Naz M, Zhang L, Chen C, Yang S, Dou H, Mann S Commun Chem. 2024; 7(1):79.

PMID: 38594355 PMC: 11004187. DOI: 10.1038/s42004-024-01168-5.

Synthesis and Biological Evaluation of Novel Amino and Amido Substituted Pentacyclic Benzimidazole Derivatives as Antiproliferative Agents.

Perin N, Gulin M, Kos M, Persoons L, Daelemans D, Fabijanic I Int J Mol Sci. 2024; 25(4).

PMID: 38396966 PMC: 10889688. DOI: 10.3390/ijms25042288.

References

Vladescu I, McCauley M, Nunez M, Rouzina I, Williams M . Quantifying force-dependent and zero-force DNA intercalation by single-molecule stretching. Nat Methods. 2007; 4(6):517-22. DOI: 10.1038/nmeth1044. View

Glass L, Bapat A, Kelley M, Georgiadis M, Long E . Semi-automated high-throughput fluorescent intercalator displacement-based discovery of cytotoxic DNA binding agents from a large compound library. Bioorg Med Chem Lett. 2010; 20(5):1685-8. PMC: 2845320. DOI: 10.1016/j.bmcl.2010.01.033. View

Zhang D, Seelig G . Dynamic DNA nanotechnology using strand-displacement reactions. Nat Chem. 2011; 3(2):103-13. DOI: 10.1038/nchem.957. View

McGhee J . Theoretical calculations of the helix-coil transition of DNA in the presence of large, cooperatively binding ligands. Biopolymers. 1976; 15(7):1345-75. DOI: 10.1002/bip.1976.360150710. View

Kielar C, Xin Y, Shen B, Kostiainen M, Grundmeier G, Linko V . On the Stability of DNA Origami Nanostructures in Low-Magnesium Buffers. Angew Chem Int Ed Engl. 2018; 57(30):9470-9474. DOI: 10.1002/anie.201802890. View

Seo S, Wang M, Shade C, Rouge J, Brown K, Mirkin C . Modulating the Bond Strength of DNA-Nanoparticle Superlattices. ACS Nano. 2015; 10(2):1771-9. PMC: 8189661. DOI: 10.1021/acsnano.5b07103. View

Busto N, Cano B, Tejido R, Biver T, Leal J, Venturini M . Aggregation features and fluorescence of Hoechst 33258. J Phys Chem B. 2015; 119(13):4575-81. DOI: 10.1021/jp512306c. View

McGhee J, von Hippel P . Theoretical aspects of DNA-protein interactions: co-operative and non-co-operative binding of large ligands to a one-dimensional homogeneous lattice. J Mol Biol. 1974; 86(2):469-89. DOI: 10.1016/0022-2836(74)90031-x. View

Zhang , Chung , OLDENBURG . A Simple Statistical Parameter for Use in Evaluation and Validation of High Throughput Screening Assays. J Biomol Screen. 2000; 4(2):67-73. DOI: 10.1177/108705719900400206. View

10.

Taniguchi J, Pandian G, Hidaka T, Hashiya K, Bando T, Kim K . A synthetic DNA-binding inhibitor of SOX2 guides human induced pluripotent stem cells to differentiate into mesoderm. Nucleic Acids Res. 2017; 45(16):9219-9228. PMC: 5766170. DOI: 10.1093/nar/gkx693. View

11.

Uno K, Sugimoto N, Sato Y . N-aryl pyrido cyanine derivatives are nuclear and organelle DNA markers for two-photon and super-resolution imaging. Nat Commun. 2021; 12(1):2650. PMC: 8113587. DOI: 10.1038/s41467-021-23019-w. View

12.

Trotta E, DAmbrosio E, Grosso N, Ravagnan G, Cirilli M, Paci M . 1H NMR study of [d(GCGATCGC)]2 and its interaction with minor groove binding 4',6-diamidino-2-phenylindole. J Biol Chem. 1993; 268(6):3944-51. View

13.

Boulais E, Sawaya N, Veneziano R, Andreoni A, Banal J, Kondo T . Programmed coherent coupling in a synthetic DNA-based excitonic circuit. Nat Mater. 2017; 17(2):159-166. DOI: 10.1038/nmat5033. View

14.

Reynaldo L, Vologodskii A, Neri B, Lyamichev V . The kinetics of oligonucleotide replacements. J Mol Biol. 2000; 297(2):511-20. DOI: 10.1006/jmbi.2000.3573. View

15.

Millan C, Acosta-Reyes F, Lagartera L, Ebiloma G, Lemgruber L, Martinez J . Functional and structural analysis of AT-specific minor groove binders that disrupt DNA-protein interactions and cause disintegration of the Trypanosoma brucei kinetoplast. Nucleic Acids Res. 2017; 45(14):8378-8391. PMC: 5737332. DOI: 10.1093/nar/gkx521. View

16.

Biebricher A, Heller I, Roijmans R, Hoekstra T, Peterman E, Wuite G . The impact of DNA intercalators on DNA and DNA-processing enzymes elucidated through force-dependent binding kinetics. Nat Commun. 2015; 6:7304. PMC: 4557362. DOI: 10.1038/ncomms8304. View

17.

Paul A, Farahat A, Boykin D, Wilson W . Thermodynamic Factors That Drive Sequence-Specific DNA Binding of Designed, Synthetic Minor Groove Binding Agents. Life (Basel). 2022; 12(5). PMC: 9147024. DOI: 10.3390/life12050681. View

18.

Chen H, Zhang H, Pan J, Cha T, Li S, Andreasson J . Dynamic and Progressive Control of DNA Origami Conformation by Modulating DNA Helicity with Chemical Adducts. ACS Nano. 2016; 10(5):4989-96. DOI: 10.1021/acsnano.6b01339. View

19.

Lee C, Kim Y, Kim K, Lee J, Kim D . Modulating the chemo-mechanical response of structured DNA assemblies through binding molecules. Nucleic Acids Res. 2021; 49(21):12591-12599. PMC: 8643692. DOI: 10.1093/nar/gkab1119. View

20.

Drapkin B, Minna J . A rational targeted therapy for platinum-resistant small-cell lung cancer. Cancer Cell. 2021; 39(4):453-456. DOI: 10.1016/j.ccell.2021.03.003. View