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Determining Physical Properties of Heterogeneous Protein Complexes in Small Volumes (PhysProt)
Start date: Feb 1, 2014, End date: Jan 31, 2019 PROJECT  FINISHED 

The objective of this proposal is to probe in aqueous solution protein complexes which are both heterogeneous and possess highly variable stoichiometries. The study of heterogeneous protein systems by conventional means is very challenging since most current biophysical methods perform best for pure solutions of isolated components - yet proteins exert in the majority of cases their biological functionality through forming complexes. We propose in this application that the key to study such systems is to operate in much smaller volumes than in conventional biophysical experiments. We will use microfluidics to obtain information about the physical properties of protein complexes in real time through quantitative micron-scale measurements of mass transport of molecular species under the action of diffusion and electric or centrifugal fields. Furthermore, by working in small volumes, we will study nucleation phenomena inherent to many protein self-assembly phenomena on the level of single nucleation events by segregating individual nuclei into spatially distinct compartments. Modern microfabrication techniques that allow for the manipulation of liquids on the picolitre scales required for this project are available and will be exploited, but the potential of this technology to define experimentally highly heterogeneous protein complexes in terms of their key fundamental physical properties, such as the hydrodynamic radius, charge and mass, and shed light on the physical basis of protein self-assembly, have remained unexploited. Using this approach, we will explore biological problems of fundamental and practical importance characterised by heterogeneity, including functional chaperone complexes, formation and detection of amyloid oligomers and studies of complex biomolecular mixtures. This programme will deliver fundamentally new approaches to study heterogeneous protein complexes and will shed light on the physical principles that govern protein self-assembly.

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