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

James S Craig, Larry Melidis, Hugo D Williams, Samuel J Dettmer, Alexandra A Heidecker, Philipp J Altmann, Shengyang Guan, Callum Campbell, Douglas F Browning, Roland K O Sigel, Silke Johannsen, Ross T Egan, Brech Aikman, Angela Casini, Alexander Pöthig, Michael J Hannon

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)13570-13580
Number of pages11
JournalJournal of the American Chemical Society
Issue number25
Early online date15 Jun 2023
Publication statusPublished - 28 Jun 2023

Bibliographical note

Copyright © 2023 The Authors. Published by American Chemical Society.


  • Cavities
  • chemical structure
  • genetics
  • gold
  • melting


Dive into the research topics of 'Organometallic Pillarplexes That Bind DNA 4-Way Holliday Junctions and Forks'. Together they form a unique fingerprint.
  • Organometallic Pillarplexes that bind DNA 4-way Holliday Junctions and Forks.

    Craig, J. S., Melidis, L., Williams, H. D., Dettmer, S. J., Heidecker, A. A., Altmann, P. J., Guan, S., Campbell, C., Browning, D. F., Sigel, R. K. O., Johannsen, S., Egan, R. T., Aikman, B., Casini, A., Poethig, A. & Hannon, M. J., 4 Jan 2023, 19 p.

    Research output: Preprint or Working paperPreprint

    Open Access

Cite this