Organometallic Pillarplexes That Bind DNA 4-Way Holliday Junctions and Forks


Holliday 4-way junctions are key to important biological DNA processes (insertion, recombination, and repair) and are dynamic structures that adopt either open or closed conformations, the open conformation being the biologically active form. Tetracationic metallo-supramolecular pillarplexes display aryl faces about a cylindrical core, an ideal structure to interact with open DNA junction cavities. Combining experimental studies and MD simulations, we show that an Au pillarplex can bind DNA 4-way (Holliday) junctions in their open form, a binding mode not accessed by synthetic agents before. Pillarplexes can bind 3-way junctions too, but their large size leads them to open up and expand that junction, disrupting the base pairing, which manifests in an increased hydrodynamic size and lower junction thermal stability. At high loading, they rearrange both 4-way and 3-way junctions into Y-shaped forks to increase the available junction-like binding sites. Isostructural Ag pillarplexes show similar DNA junction binding behavior but lower solution stability. This pillarplex binding contrasts with (but complements) that of metallo-supramolecular cylinders, which prefer 3-way junctions and can rearrange 4-way junctions into 3-way junction structures. The pillarplexes' ability to bind open 4-way junctions creates exciting possibilities to modulate and switch such structures in biology, as well as in synthetic nucleic acid nanostructures. In human cells, the pillarplexes do reach the nucleus, with antiproliferative activity at levels similar to those of cisplatin. The findings provide a new roadmap for targeting higher-order junction structures using a metallo-supramolecular approach, as well as expanding the toolbox available to design bioactive junction binders into organometallic chemistry.

Publication DOI:
Divisions: College of Health & Life Sciences > School of Biosciences
Funding Information: This work was funded by the EPSRC Physical Sciences for Health Centre (EP/L016346/1) BBSRC MIBTP (BB/M01116X/1), DFG-SPP 1928, the Swiss National Science Foundation (200020_165868; 200020_192153) University of Zurich, and the University of Birmingham. Sim
Additional Information: Copyright © 2023 The Authors. Published by American Chemical Society.
Uncontrolled Keywords: Cavities,chemical structure,genetics,gold,melting
Publication ISSN: 1520-5126
Last Modified: 11 Jul 2024 07:23
Date Deposited: 20 Jun 2023 15:28
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Related URLs: ... 21/jacs.3c00118 (Publisher URL)
http://www.scop ... tnerID=8YFLogxK (Scopus URL)
PURE Output Type: Article
Published Date: 2023-06-28
Published Online Date: 2023-06-15
Accepted Date: 2023-01-04
Authors: Craig, James S
Melidis, Larry
Williams, Hugo D
Dettmer, Samuel J
Heidecker, Alexandra A
Altmann, Philipp J
Guan, Shengyang
Campbell, Callum
Browning, Douglas F (ORCID Profile 0000-0003-4672-3514)
Sigel, Roland K O
Johannsen, Silke
Egan, Ross T
Aikman, Brech
Casini, Angela
Pöthig, Alexander
Hannon, Michael J



Version: Published Version

License: Creative Commons Attribution

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