PHOTOMASS · Imaging Biomolecular Self-Assembly with a Molecular Photonic Scale

We propose to transform our understanding of biomolecular interactions and self-assembly by directly visualising the associated molecular mechanisms. To achieve this, we will capitalise on our recent development of interferometric scattering mass spectrometry (iSCAMS), which enables not only the detection and imaging of single biomolecules in solution, but also the accurate determination of their molecular mass at the single molecule level. These studies, and the development of the associated technology, will bridge the gap between high-resolution structural and low-resolution solution-based methods for studies of biomolecular interactions and assembly. We will achieve these ambitious goals by pursuing five interconnected objectives chosen according to their potential to maximise scientific and societal impact by addressing fundamental questions related to biological function and health: (1) Determine the physicochemical origins of mono- and polydispersity; (2) Visualise the mechanism of viral capsid assembly; (3) Reveal the molecular basis of cytoskeletal dynamics; (4) Capture the aggregation and inhibition of amyloid aggregation. These four system-oriented objectives will be accompanied by a technological objective, (5) aimed at implementing improvements in terms of dynamic range and resolution of iSCAMS required for studying self-assembly. As a consequence of the universal applicability of our approach for characterising molecular interactions, oligomeric distributions and dynamics in a facile fashion in solution, this ambitious project opens up a broad range of exciting applications beyond molecular biophysics in fields as drug-discovery, bioanalytical and biomedical science.