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.

doi:10.1101/2023.01.04.522759

bioRxiv · 10.1101/2023.01.04.522759

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.

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Abstract

Holliday 4-way junctions are key to important biological DNA processes (insertion, recombination and repair) and are dynamic structures which adopt either open or closed conformations, with the open conformation being the biologically active form. Tetracationic metallo-supramolecular pillarplexes display aryl faces about a cylindrical core giving them an ideal structure to interact with the central cavities of open DNA junctions. Combining experimental studies and MD simulations we show that an Au pillarplex can bind DNA 4-way junctions (Holliday junctions) in their open form, a binding mode not accessed by synthetic agents before. The Au pillarplexes can bind designed 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 increase in hydrodynamic size and a lower junction thermal stability. At high loading they re-arrange both 4-way and 3-way junctions into Y-shaped DNA forks to increase the available junction-like binding sites. The structurally related Ag pillarplexes show similar DNA junction binding behaviour, but a lower solution stability. This pillarplex binding contrasts with (but complements) that of the metallo-supramolecular cylinders, which prefer 3-way junctions and we show 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 where they are key interconnecting components. Studies in human cells, confirm that 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. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=188 SRC="FIGDIR/small/522759v1_ufig1.gif" ALT="Figure 1"> View larger version (43K): org.highwire.dtl.DTLVardef@10fac36org.highwire.dtl.DTLVardef@1f32f9forg.highwire.dtl.DTLVardef@bb8d72org.highwire.dtl.DTLVardef@1433de5_HPS_FORMAT_FIGEXP M_FIG C_FIG

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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.. 2023-01-04. Organometallic Pillarplexes that bind DNA 4-way Holliday Junctions and Forks.. https://doi.org/10.1101/2023.01.04.522759

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