Frank Sobott

Chair of Biomolecular Mass Spectrometry (Astbury Centre, Leeds)

Research themes

Major advances in mass spectrometry over the past two decades have secured it a central role in chemical and biological research, from structure elucidation of small molecules to analysis of conformation and architecture of large protein and DNA/RNA complexes. Our research has made contributions to many of these developments at various stages over almost two decades; both from the side of instrument and method development, and also by pioneering applications of these tools in collaboration with scientists working on supramolecular systems as well as molecules of biochemical and biomedical interest. “Native” mass spectrometry is increasingly becoming an essential component of the drug discovery and development process, from ligand binding studies to biopharmaceuticals characterization and membrane protein stability and inter-actions screens.

Our research is aimed at development and applications of methods based on “native” mass spectrometry (MS), ion mobility (IM) and associated structural proteomics techniques, in order to understand and characterize noncovalent interactions in chemistry and biology. We are particularly interested in analyzing key biomolecular complexes which are at the nodes of the intricate network of protein interactions in the cell. Our current projects include the investigation of assembly and disassembly of protein complexes in response to conformational and post-translational modification states, the effect of ligand binding (e.g. drug candidates), and their link with structure and function. We are also developing experimental and computational approaches for the characterization of intrinsic disorder in proteins, an important phenomenon which occurs in large parts of the proteome, but is almost intractable with most conventional structural biology techniques. Particularly challenging, but also of high significance is the study of conformation and assembly of integral membrane proteins and pore-forming peptides, which we investigate using various different approaches including detergent micelles, bilayers and nanodiscs.

We are employing a combination of cutting-edge technologies such as ion mobility in conjunction with high resolution tandem mass spectrometry under “native” conditions to obtain information on subunit architecture and stoichiometry as well as size and shape of non-covalent complexes and assemblies. We are also developing advanced “top-down” fragmentation techniques such as Electron Transfer Dissociation (ETD) and Surface Induced Dissociation (SID), for the structural investigation of large molecules and the dissection of noncovalent interfaces, in collaboration with instrument manufacturers. Other tools developed in my laboratory aim at generating profiles of the solvent-accessible surface area of such biomolecular aggregates, in order to generate restraints for computational approaches such as structure modelling and prediction.

The overarching theme of our research programme is the development and application of novel tools for supramolecular chemistry, high-throughput structural proteomics and integrated structural biology. More generally, we are interested in the characterization of noncovalent assemblies both in solution and the gas phase, and in studying the deposition of biomolecules and other complex structures on surfaces. Our group also collaborates widely and internationally with colleagues in academia and industry, particularly instrument manufacturers and pharmaceutical/ biotech companies.

Our current research programme strives to strike a balance between the pursuit of new concepts, ideas, and high-profile targets on one side, and the broader implementation and application of a  raft of mass spectrometry-related approaches on the other, with the aim to create an analytical toolbox which is used in a highly collaborative context.

Mission

The focus of our research is on the analysis of noncovalent interactions in supra-molecular systems and large functional assemblies of biomolecules.

We are developing new methods and instrumentation for the analysis of multi-component, heterogeneous and dynamic assemblies based on mass spectrometry and ion mobility spectrometry and associated techniques.

We apply these tools in a highly interdisciplinary context to research questions from chemistry, biology and medicine.