... understanding life in molecular detail

Prof Frank Sobott

Mass Spectrometry, Ion Mobility Spectrometry, Structural Proteomics, Biomolecular Analysis

My group develops and applies new mass spectrometry methodologies to the analysis of the structure and functional behaviour of biomolecules and biomolecular complexes.

Current major projects include:
  • protein conformational studies and assembly e.g. amyloid aggregation
  • membrane protein and lipid interactions analysis
  • ligand binding studies and top-down protein characterization
  • oligonucleotide structure & function

The focus of my research is on the structural analysis of noncovalently bound, supramolecular systems and 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 and associated techniques. We apply these tools in a highly interdisciplinary context to research questions from chemistry, biology and medicine.

 Mass spectrometry

My 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. I am particularly interested in analyzing key biomolecular complexes which are at the nodes of the intricate network of protein interactions in the cell. Current projects include the investigation of assembly and disassembly of protein complexes in response to conformational and posttranslational modification states, the effect of ligand binding, and the link with structure and function. The group is also developing experimental and computational approaches for the characterization of intrinsic disorder in proteins, an important phenomenon which occurs in parts of the proteome, but is almost intractable with many 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.

Using a combination of cutting-edge technologies, such as ion mobility in conjunction with high resolution tandem mass spectrometry under “native” conditions, allows obtaining information on subunit architecture and stoichiometry as well as size and shape of non-covalent complexes and assemblies. We also develop advanced “top-down” fragmentation techniques such as Electron Transfer Dissociation (ETD) for the structural investigation of large molecules and the dissection of noncovalent interfaces. This work aims 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.

Novel lines of research currently being established aim to work towards bridging the gap between detailed structural studies on recombinant proteins, and their corresponding behaviour in complex, cellular contexts, utilizing the capabilities of limited digests combined with high-resolution MS and FPOP to provide detail of protein structure and interactions even in live cells. We will develop tools which target structural detail and sub-us to ms dynamics using methods which are sensitive to secondary structure and surface exposure (limited digests in combination with high-resolution MS, H/D exchange and fast photochemical oxidation of proteins, FPOP). Further to these analytical approaches, I will develop preparative mass spectrometry which utilizes "soft landing" for functionalization of surfaces, but also enables subsequent high resolution structural investigation of deposited particles using various different molecular imaging techniques.

The overarching theme of my 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. The group collaborates widely and internationally with colleagues in academia and industry, particularly instrument manufacturers and pharmaceutical/ biotech companies.

Detailed research programme                  Close ▲

Chair of Biomolecular Mass Spectrometry (Feb 2017 - present)
PhD (Frankfurt) Postdoc (Oxford)

Team Leader Molecular Biophysics, Oxford (2004-2007)
Senior Scientist/PI, Oxion and Biochemistry Dept., Oxford (2007-2009)
Francqui Research Professor, Antwerp (2011-2014)
Associate Professor, Antwerp (2009-2017)

Astbury 8.110
School of Molecular and Cellular Biology
0113 343 2576

Selected Publications

  1. A. Konijnenberg, S. Ranica, J. Narkiewicz, G. Legname, R. Grandori, F. Sobott*, A. Natalello*. Opposite structural effects of epigallocatechin-3-gallate and dopamine binding to α-synuclein. Anal. Chem., 88 (2016), 8468

  2. A. Konijnenberg, D. Yilmaz, H.I. Ingólfsson, A. Dimitrova, S.J. Marrink, Z. Lid, C. Vénien-Bryan, F. Sobott*, A. Koçer*. Global structural changes of an ion channel during its gating are followed by ion mobility mass spectrometry. Proc. Natl. Acad. Sci. USA, 111 (2014), 17170

  3. F. Lermyte, A. Konijnenberg, J.P. Williams, J.M. Brown, D. Valkenborg, F. Sobott. ETD allows for native surface mapping of a 150 kDa noncovalent complex on a commercial Q-TWIMS-TOF instrument. J. Am. Soc. Mass Spectrom. 25 (2014), 343

  4. R.M. Smith, J.J. Marshall, A.J. Jacklin, S.E. Retter, S.E. Halford, F. Sobott. Organization of the BcgI restriction-modification protein for the cleavage of eight phosphodiester bonds in DNA. Nucleic Acids Res. 41 (2013), 391