GlasBioPhys: an integrated facility for the analysis of biomolecular interactions

Understanding the structure and functions of biomolecules is essential if we are exploit them for medical and industrial applications. Biomolecules such as proteins, drugs, DNA and RNA all rely on a series of weak (non-covalent) bonds, which work in concert to form specific molecular complexes. These non-covalent interactions are key to all biological processes such as how genes are switched on by proteins, how enzymes function, how molecular machines assemble inside cells and how drugs work. Our understanding of this requires the use of a range of complex equipment, often requiring several pieces of equipment to fully characterize a biomolecule, such as Surface Plasmon Resonance to measure how much affinity biomolecules have for each other or the rates at which they bind to each other. We often use a technique called Isothermal Titration Calorimetry to determine the thermodynamics of interaction and fluorescence polarization spectroscopy to report on how proteins change their conformation when they interact with a partner. These instruments all measure biomolecule interactions in isolation, they are low-throughput and require the development and isolation of experimental conditions for each technique.

This application proposes to establish a UK wide facility to measure all of these interactions within a single instrument (switchSENSE heliX, launched in October 2019). At present, there is no existing infrastructure which can match the capabilities of the SwitchSENSE heliX instrument currently on the market. We proposed to use this to support established BBSRC funded academic researchers and industrial partners in Glasgow and more widely in the UK. These researchers will use the SwitchSENSE helix to investigate DNA-binding interactions with drugs, DNA and RNA-binding and how this affects gene expression, post-translational modification of proteins and protein-protein interactions all possible in a streamlined high-throughput fashion. In addition, this grant will facilitate the training of researchers, supporting the training of doctoral students and also access to the equipment by industry to help build the UK capability and sustainability in the area of biomolecular interactions.

Knowledge of the strength and driving forces underpinning biomolecular interactions is essential to understand biomolecule structure and function. Binding affinity and kinetics provide information concerning the strength of a binding interaction and the rate of association/dissociation, the thermodynamics enhances our understanding of the origins of the forces driving molecular recognition. Since biomolecules are not static entities, the dynamic changes of a biomolecule upon binding provides additional information on how interactions influence function. Thus, there is a critical need for tools and technologies which can quantify biomolecular interactions in a streamlined and high-throughput fashion and this will benefit a range of scientists.

Basic scientists: Studies and characterisation of biomolecules can inform us on a host of aspects related to the interplay of structure-function-dynamics analysis. The work proposed here also will inform us on the basic science behind the interaction and biophysical properties of a wide range of biomolecules. This work will be of interest to a wide community of researchers (Biochemists, biophysicists, microbiologists, evolutionary biologists, genomics scientists etc) who study a range of systems and organisms, but particularly to those who work in DNA-binding, RNA-binding, gene expression, post-translational modification of proteins, protein-protein interactions, drug-ligand interactions and drug discovery.

Applied scientists and industrial and development scientists: This work can aid in the development of methods to develop new drugs and therapeutics and also on the basic biology of drug targets. The data from the SwitchSENSE helix will find utility in enzyme screening for biocatalysis and biotransformations in industry enabling prioritisation of targets and screening of enzyme libraries.

A long-term and continued investment in biomolecular sciences from UKRI has continued to make a significant impact on the UK economy and on industry and human and animal health. The investment from UKRI in the applicants of this proposal has also trained and supported a highly-skilled work force in the UK and internationally. This proposal will have impact in BBSRC priority areas such as healthy aging across the life course, industrial biotechnology, combatting antimicrobial resistance, bioenergy and animal health. The continued training of early career researchers in this field is key to continued exploitation and translation of biophysical data in to application. High quality training, mentorship and development programmes for researchers is required for capacity building in this area.

Industrial applications: The industrial biotechnology market in the UK has recently been estimated at £81 billion per annum, employing 800,000 people across the pharmaceutical, food & drink, bioconversion and waste-treatment industries. The applicants have long standing industrial links with companies engaged in the development of a rage of processes including DNA-binding interactions with drugs, DNA and RNA-binding and how this affects gene expression, post-translational modification of proteins and protein-protein interactions. BBSRC-funded projects which include alternative RNA splicing (Burley), protein S-acylation (Chamberlain), bio-diagnostics for detection food-based pathogens (Faulds) and industrial-scale antibiotic production (Hoskisson) will considerably benefit from the acquisition of this instrument. These long-term and continued industrial links demonstrate that the applicants are able to realise the potential of discoveries and to implement these in a form that will be attractive to industry.

Outreach/public engagement: Research in the area of biomolecular interactions and biophysical analysis have impact in areas that all stakeholders in research are invested and can be transformed in to tangible outputs for industry, agriculture and human health. The programme developed here will engage the public at a range of levels (outreach events, social media and stop-motion animations) to reinforce the impacts of the work.