Switchable & Biomimetic Self-Assembly of Guanosines: Characterising the Interplay of Structure-Directing Non-Covalent Interactions by Solid-State NMR

Lead Research Organisation: University of Warwick
Department Name: Physics


Nature exploits the interactions between organic molecules to perform the functions of life, e.g., the manufacture of proteins by reading the code of our DNA or the pumping of metal ions in and out of a cell through ion channels in the cellular membranes. Chemists are striving to understand how to mimic this fine control over the intermolecular interactions that drive how specific molecules assemble together. This project focuses on synthetic derivatives based on guanosine that is one of the constituents of DNA. Over the last 15 years, a wide variety of such compounds have been synthesised in laboratories across the world which exhibit a rich diversity of nanostructures. These systems have the potential to be exploited as novel materials, e.g., in molecular electronic devices, or to extract specific ions, e.g., radioactive caesium, or in the construction of biomimetic ion channels. Of particular interest are smart materials, where the adopted self-assembly can be altered by an external stimulus, e.g.,light.
The availability of analytical tools to view specific intermolecular interactions is a pre-requisite for the informed design of new materials and biomimetic systems. Of key importance are so-called hydrogen bonds where a hydrogen atom (H) is shared between an acceptor atom, e.g., oxygen (O) or nitrogen (N) and a donor group, e.g., OH or NH. Observing such interactions is particularly challenging in the solid state for guanosine derivatives which are usually composed of a rigid core with attached flexible chains whose dynamics prevents the determination of the 3D structure using the widely employed method of X-ray diffraction, while surface-based imaging techniques lack the resolution to view the intermolecular interactions.
Instead, this project makes use of the technique of nuclear magnetic resonance (NMR), which exploits the inherent magnetism of atomic nuclei. In very strong magnetic fields that are a few hundred thousand times stronger than the Earth's magnetic field, the nuclear magnetic moments can be induced to change their alignment with respect to the external magnetic field using the energy associated with radio waves of a specific frequency. Measuring these frequencies reveals intricate details about, first, the electronic environment of an atomic nucleus and hence its chemical structure and, second, how the different magnetic moments are arranged, allowing distances between atoms to be measured very accurately. While most NMR experiments are performed on liquid samples, where the tumbling of the molecules increases the resolution of different spectral lines, solid-state samples can be analysed using a method called magic-angle spinning (MAS) whereby the sample is rotated rapidly around an axis inclined at an angle of 54.7 degrees to the external magnetic field.
In preliminary work, using MAS solid-state NMR, the Warwick group have shown that two different types of self-assembly exhibited by guanosine derivatives, namely ribbon-like and quartet-like arrangements, can be distinguished. Working together with two leading overseas groups who pioneered the research field of synthetic guanosine derivatives and are at the forefront of demonstrating new applications, this project will systematically investigate how changing the solvent, pH, or temperature affects the exhibited self-assembly. A particular focus will be derivatives that exhibit tunable self-assembly and form biomimetic ion channels. Experiments will be carried out using state-of-the-art infrastructure including the UK 850 MHz solid-state NMR facility. By comparing the new insight provided by solid-state NMR to that obtained previously in the solution-state and on surfaces, the factors determining similarities and differences between how self-assembly is controlled in different phases (solid vs.solution) and bulk vs surface effects will be elucidated. By establishing structure-property relationships, this will enable the design of better new materials.

Planned Impact

Work in academic laboratories is showing how the versatile self-assembly of synthetic guanosine derivatives can be exploited to generate novel nanostructures that can be switchable, with demonstrated applications exhibiting the properties required for molecular electronics, ion extraction and the forming of biomimetic ion channels. There is clear potential to exploit this in the future in the commercial production of stimuli-responsive devices. Moreover, linking to related work in the area of chemical biology using oligonucleotides to target and disrupt protein-protein interactions opens up the possibilities of pharmaceutical advances, e.g., designing protein-protein inhibitors. These end-user applications motivate the proposed research that, in providing an atomic-level characterisation of the intermolecular interactions that control self-assembly in the solid and also gel/solid state, aims to provide the underpinning understanding that is a pre-requisite for the informed design of novel materials, biomimetics and pharmaceutical treatments.
The hydrogen bonding and CH-pi intermolecular interactions that drive self-assembly of guanosine derivatives are fundamental in also governing the solid-state structures adopted by other organic molecules. Thus, the specific new insight provided by this project has much wider applicability, for example to the characterisation and control of polymorphism exhibited by active pharmaceutical ingredients (that are typically small molecules containing heterocyclic moieties like that in guanosine), and understanding the polymorphism observed in amyloid fibrils, associated with, e.g., Alzheimer's disease, as well as how oligomer to polymer transitions are driven at interfaces, including protein interfaces. Indeed, a further similarity to this project in these cases is that it is often also not possible to obtain single crystals suitable for X-ray diffraction. Thus, further benefit can be obtained from a transfer of know-how associated with the demonstrated ability of advanced solid-state NMR methods to provide an atomic-level characterisation of the key intermolecular interactions.


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Peters GM (2014) A G4·K? hydrogel stabilized by an anion. in Journal of the American Chemical Society

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Peters GM (2015) G4-quartet·M(+) borate hydrogels. in Journal of the American Chemical Society

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Reddy GN (2015) An NMR crystallography study of the hemihydrate of 2', 3'-O-isopropylidineguanosine. in Solid state nuclear magnetic resonance

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Reddy GN (2017) Co-existence of Distinct Supramolecular Assemblies in Solution and in the Solid State. in Chemistry (Weinheim an der Bergstrasse, Germany)

Description A key highlight was showing a molecule self-assembling into different forms when passing between solution state to solid state, and back again - a curious phenomenon in science. Specifically, the supramolecular structure of a guanosine derivative was shown to be different upon passing from the solid state into the solution state and vice versa.
This defies chemical precedent, as self-assembled structures driven by the formation of specific intermolecular hydrogen bonds in solution would be expected to remain the same in the solid state. The phenomenon was revealed by the state-of-the-art nuclear magnetic resonance (NMR) facility at Warwick. In solution state, the guanosine derivative analysed by the researchers is constituted by quartet-like molecular structure - and scientific intuition would suggests that this should remain like this in the solid state. However, upon changing into the solid state, the supramolecular assembly surprisingly contains both quartet and ribbon structures.
Exploitation Route The observations have importance for scientists looking at crystallization and dissolution, or with interest in how specific interactions, e.g., hydrogen bonding drive self assembly. The results showcase the power of advanced solid-state magic-angle-spinning methodologies.
Sectors Chemicals,Pharmaceuticals and Medical Biotechnology

URL https://warwick.ac.uk/newsandevents/pressreleases/molecular_phenomenon_discovered/
Description The experimental NMR and computational results for supramolecular systems reported in published papers from this research have wider importance, for example for pharmaceuticals
First Year Of Impact 2015
Sector Pharmaceuticals and Medical Biotechnology
Impact Types Economic