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

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 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 ability of pillarplexes 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

Birmingham Environment for Academic Research : Case studies volume 3

This collection of case studies was brought together to showcase the extent and diversity of research that is supported by the University of Birmingham’s Environment for Academic Research (BEAR). BEAR is a collection of contemporary IT resources designed to help research. The following case studies demonstrate how BEAR services such as the Research Data Store (RDS), BEAR software and the University supercomputer BlueBEAR are integral to the progression of important research across disciplines. BlueBEAR is a key component of BEAR, providing compute power and specialist applications free to enable staff and students to delve deeper into their research. Upgraded in 2023, the cluster includes many large memory nodes and a GPU service alongside standard compute nodes. Alongside BlueBEAR, the RDS is a popular choice amongst researchers to securely store their working research data. As of publication, more than 5000 researchers across all five colleges were actively using BlueBEAR and/or the RDS. In this volume, we showcase case studies representing diverse research from every college. From estimating snow coverage to modelling second language acquisition, we show how BEAR services are enabling exciting and important research across the university

Raw dataset for submitted publication Recognition of a DNA Four Way Junction by an M2L4 Supramolecular Metallocage, Inspired by a Simulation-Guided Approach

In this repository you will find: Original, unedited gel images shown in this work in TIF format. Original, unedited UV-VIS data in csv format. Original, unedited NMR data. Original, unedited mass spec data, compatible with MassLynx software. Simulation data including: All coordinate files for the compounds simulated; All simulations in .xtc format with corresponding .pdb or .gro starting frames, .tpr run files and .ndx index files Simulation files have been outputted with 1 ns per frame and waters removed to maintain reasonable file sizes. Representative videos of the simulations

Birmingham Environment for Academic Research:Case studies volume 3

This collection of case studies was brought together to showcase the extent and diversity of research that is supported by the University of Birmingham’s Environment for Academic Research (BEAR). BEAR is a collection of contemporary IT resources designed to help research. The following case studies demonstrate how BEAR services such as the Research Data Store (RDS), BEAR software and the University supercomputer BlueBEAR are integral to the progression of important research across disciplines.BlueBEAR is a key component of BEAR, providing compute power and specialist applications free to enable staff and students to delve deeper into their research. Upgraded in 2023, the cluster includes many large memory nodes and a GPU service alongside standard compute nodes. Alongside BlueBEAR, the RDS is a popular choice amongst researchers to securely store their working research data. As of publication, more than 5000 researchers across all five colleges were actively using BlueBEAR and/or the RDS. In this volume, we showcase case studies representing diverse research from every college. From estimating snow coverage to modelling second language acquisition, we show how BEAR services are enabling exciting and important research across the university