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ERC

COSIMO Report Summary

Project ID: 294443
Funded under: FP7-IDEAS-ERC
Country: United Kingdom

Final Report Summary - COSIMO (COVALENT SINGLE-MOLECULE CHEMISTRY OF THE CELL)

Our major effort has been in single-molecule covalent chemistry detected in protein nanoreactors, an innovative means to monitor the making and breaking of individual chemical bonds. In this approach, the nature of reaction steps occurring within the lumen of a transmembrane pore is reflected in changes in an ionic current flowing through the pore.

The work has been exceedingly fruitful and most of the objectives in the proposal, or variations of them, have been accomplished. The most striking achievements have been in the area of molecular walkers, in which molecules move along engineered tracks. Our 2014 publication in Nature Nanotechnology was a breakthrough in this area. It described the movements of a small molecule walker along a track in steps of 0.6 nm, each taking about 700 milliseconds, which is unprecedented spatiotemporal resolution.

Additional work on single-molecule chemistry has included the investigation of complex reaction networks, one featuring an extraordinary 38 possible interconversions. Further, several protein engineering studies have been made in support of our investigations of single-molecule covalent chemistry. For example, the chemistry that can be examined by the nanoreactor approach has been greatly expanded by building nanoreactors from protein subunits obtained by native chemical ligation in which unnatural amino acids with a variety of reactive side chains are used.

The rapid progress on single-molecule chemistry has allowed us begin the exploration of additional frontline projects. For example, the success of Oxford Nanopore's MinION sequencer suggested that a similar instrument might be used to investigate aspects of the proteome, notably the detection of post-translational modifications and polypeptide splice forms. Indeed, we have now used nanopore detection to identify phosphorylation sites in a protein.

Another exciting new area, which we have initiated during the funding period, is the building of synthetic tissues by 3D printing. The materials consist of picoliter droplets separated by single lipid bilayers into which our engineered pores can be incorporated. One long-term goal is to remotely control the properties of synthetic tissues by spatially structured stimuli, and to this end light-patterned electrical signaling within a tissue has already been demonstrated.

The ERC funding has allowed work in a highly cross-disciplinary area, involving graduate students and postdoctoral associates from varied backgrounds, e.g. chemistry, biochemistry, physics and engineering. We have been able, therefore, to focus on solving the problem at hand, rather than the application of a single expertise over and over again. During the funding period, in 2014, a spin-out company, OxSyBio (http://www.oxsybio.com), was established, based in part on work supported by the ERC.

Reported by

THE CHANCELLOR, MASTERS AND SCHOLARS OF THE UNIVERSITY OF OXFORD
United Kingdom
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