ABOUT
The Chemistry of Life Theme aims at advancing the most challenging questions in the life sciences. We are proponents of taking a chemical view of biology. We believe that a comprehensive understanding of biology requires drilling down to the minutiae of molecular interactions. To achieve these goals, it is necessary to employ methods that work on different time scales (femtosecond to second) and length scales (Ångström to micrometre). Holistic approaches are widely used in physical sciences, where experiments in the frequency domain reveal molecular states or resonances, and those in the time domain reveal the energy re-distribution; and where calculations using classical mechanics simulate molecular motions, and those using ab initio approaches simulate quantum- mechanical phenomena. However, these types of comprehensive studies are much rarer in the Life Sciences. We also recognise the potential to deploy bespoke molecules (designed and synthesised by chemists) to probe and modulate outcomes, and thereby provide greater understanding of molecular transformations and interactions in biology. By combining multiple experimental approaches, we will be able to address questions that are beyond the reach of individual techniques. We will also encourage experimental findings to be supported by computational modelling and simulations.
CORE GROUP
GUEST RESEARCHERS
WORKING GROUPS FOR CHEMLIFE
Chemlife working group 1
Structure, function and dynamics of macro-molecular complexes
WG 1 aims to study the structure, dynamics and function of macromolecular complexes. A technique that will be at the forefront of the research in this working group will be small-angle scattering of both X-rays and neutrons (SAXS and SANS). We will also take advantage of the cryo-electron microscopy to investigate the structure of protein/protein and protein/nucleic acid complexes. In particular, we will facilitate research activity that complements results from cryo-EM with neutron and X-ray studies, and computational simulations, in order to provide important structural data alongside the dynamic information obtained by SAXS and SANS, as well as nuclear magnetic resonance (NMR) spectroscopy. Researchers at the University of Leicester have pioneered the combination of NMR spectroscopy and bioimaging (including, but not limited to, single-molecule imaging) for characterising the complexes formed between pre-mRNA and proteins in various stages of the complex reactions that determine the selection of alternative splicing. We will encourage a more ambitious methodology in WG1 by expanding the toolkit to SAXS, SANS and cryo-EM, where possible. A new area of interest of WG1 will be intrinsically disordered proteins (IDPs) and intrinsically disordered regions (IDRs) - this topic dispels the commonly held view that 3D structure is always essential for functional activity. These protein regions have eluded characterization by cryo-EM or X-ray/neutron crystallography but are amenable to SAXS, SANS, NMR, and single molecule and computational approaches.
chemlife WORKING GROUP 2
Modulating the function and activity of both macro-molecules and small molecules of life using chemical biology
One of the defining features of chemical biology is the design and application of small-molecule ligands as chemical probes to study biology. Chemical probes that are designed to exhibit high affinity and selective interactions with either a specific macromolecule, or a small biomolecule, can facilitate the study of phenotypes associated with these and their role in biology. WG2 will encompass the design and application of chemical probes to study the important biomolecules of life, from the larger macromolecular protein complexes that regulate gene transcription and RNA splicing to the smallest organic molecules such as glucose and formaldehyde. Topics within the working group will exploit the latest and most recent developments in chemical biology including protein-protein interactions, targeted protein degradation, and structure-based ligand design. The scope of this working group extends beyond drug design and pharmaceutical compounds, encompassing molecular glues, molecular probes and other bioactive compounds.
chemlife WORKING GROUP 3
The Role of metals and small molecules in biology
Metal ions are essential for many biochemical processes. The natural selection of certain metals for specific physiological roles represents a true marriage of chemistry and biology. From a biological perspective, the intrinsic properties of the ‘selected’ metal enable vital chemistry to take place efficiently, often with minimal or no additional thermodynamic driving force required. From a chemical perspective, the 3D structure and coordination environment provided by a protein is responsible for fine-tuning the properties of the metal centre to bias reactivity in favour of the desired outcome. Nature often repurposes both metals and coordination environments in order to achieve a wide range of chemical reactivity from structurally similar building blocks. WG3 will address these differences in function and reactivity, pioneering the use of complementary, and often concurrent, structural and spectroscopic methods to address problems in the chemical biology of metals.
An ability to control reactivity is becoming increasingly important if the biophysical community is to exploit fully the power of next generation X-ray, neutron, and XFEL sources. This working group will develop and promote the use of novel sample environments including, but not limited to, the use of electrochemistry to prepare specific catalytic intermediates, and the combination of stopped-flow and freeze quench methods to catch enzymes in the act. WG3 will also initiate discussion of different ways to trigger an enzyme reaction, and the best data collection strategies for catching elusive intermediates. To gain a deeper understanding of the molecular mechanisms, we will combine the experimental methods with computational simulation and analyses.
Chemistry of Life Core Group leader, LINXS Fellow
Andrew Hudson, Professor of Biophysical Chemistry, Institute for Structural and Chemical Biology, University of Leicester, UK.
Prof Hudson is a biophysical chemist with research interests in the application of specialised techniques in fluorescence imaging to monitor the dynamics of single molecules. He has been applying these methods to address otherwise inaccessible problems in RNA splicing. These have included validation of the spice-site selection model and the pathways for the early stages of spliceosome assembly and 3′ splice-site selection. On a different note, he has applied a number of different imaging modalities to quantifying the distribution of haem proteins in living cells, and how this evolves in response to different stimuli. Recently, he has been looking at the regulatory role of haem in cells, and designed a genetically-encoded sensor for measuring in vivo haem concentrations by fluorescence lifetime imaging. His research group has also developed new fluorescence assays to probe the role of haem in the molecular mechanism of the transcription-translation feedback loops which are responsible for maintaining circadian rhythms.