Physics of Life - Noise, Information and Evolution in Protein Binding

Lead Research Organisation: University of York
Department Name: Physics

Abstract

How does order emerge from chaos? As if the 'miracle of life' in all its complexity were not enough to astonish us, the molecular story of how the information and energy flows occur within living cells and organisms tells an even stranger tale. For at the dimensions of life's molecular building blocks - the long protein molecules that fold up perfectly into functional forms, the even longer DNA that codes for the structure of its organisms, the cell membranes that marshal biochemical traffic between the cell and its surroundings - all these are subject to continual, rapid random fluctuation. The thermal jostling of every component seems, at first, to fight against the appearance of the order and structure that are the emergent signs of life. However, recent interdisciplinary collaborations between physicists and biologists have begun to discover just how deeply life has evolved to work with the noisy fluctuations rather than to fight them.

This project will devote 5 years of focussed research to explore in detail three fundamental ways in which randomness and noise are recruited in biology, bringing the experience of the proposed Fellow, two post-doctoral research fellows and an extensive community of collaborators, to bear.

The first example is right at the heart of information-processing in cells. 'Allostery' is the effect by which a protein molecule binds to another molecule (either a smaller species, or a giant molecule like DNA) if and only if a second 'signalling' molecule is also bound to it, at a different site. The presence of the signalling molecule is felt 'at a distance' at the other binding site. We will develop theoretical and computational tools to explore how the background of thermal fluctuations can be used to carry the signal, and learn from biology about the physics of fluctuating elastic matter.

The second example continues the theme of protein-binding, but now to other proteins. The outstanding properties of spider and silkworm silk are even more outstanding when we discover how the fibres are made in nature. Somehow the molecular 'stickiness' of silk proteins is just enough to trigger their assembly into fibres when just the right flow conditions apply (at the spinneret). Working closely with experimental colleagues, we will develop theories of assembly in flow to help find out what makes silk, and its processing, so remarkable.

A third stream of work takes the idea of random motion but now at the higher level of evolution itself. The search for the protein structures that deliver the binding properties of signalling and silk takes place in an unimaginably vast space of possibilities coded by the organism's genome. Random jumps in this space, like the random motions of the proteins themselves, somehow serve to find solutions, rather than frustrate them. We have an exciting opportunity to use the methods of 'noisy physics' at the molecular level to explore the physics of evolution itself, asking the question. 'How does nature search for, and find solutions?'. Completing the circle of the project, we will construct theories for the evolution of the sticky proteins themselves.

Planned Impact

There are beneficiaries beyond academia, as preparation of pathways to impact has indicated. WS1 on the fluctuation route to protein allostery has strong applications in the area of drug discovery beyond structural design. Pharmaceutical companies such as GSK (contact through SOFI-CDT) and AZ (contact through Durham tech transfer) are examples. This occurs through routes including protein complexes, previously 'undruggable' pathogens and trans-membrane proteins. Research groups working in the intermediate space between this fundamental biological physics and pharmaceutical application (e.g. EMBL Hinxton - see PtoI) are also beneficiaries.
WS2 has long-term promise in the biomimetics of materials science, especially in high performance fibre technology. If together with experimental collaborators we can elucidate the joint molecular and complex flow-field optimisation of fibre formation through self-assembly then process design in advanced fibres may be assisted in taking a significant step. These beneficiaries are also accessed directly through the SOFI-CDT industrial consortium and (via the Sheffield group) the Sheffield Polymer Centre.
The work-stream on evolution WS3 has potential impact in the same biomolecular-design area as WS1 by creating tools, inspired from the complex energy landscape field, for the exploration of the complex fitness landscape of the genome. It also has considerable potential impact within the public communication of science.

Publications

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Lorimer GH (2018) Allostery and molecular machines. in Philosophical transactions of the Royal Society of London. Series B, Biological sciences

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McLeish T (2018) The 'allosteron' model for entropic allostery of self-assembly. in Philosophical transactions of the Royal Society of London. Series B, Biological sciences

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Shoshana J. Wodak (2019) Allostery in Its Many Disguises: From Theory to Applications in Structure

Related Projects

Project Reference Relationship Related To Start End Award Value
EP/N031431/1 01/02/2017 31/01/2018 £1,412,260
EP/N031431/2 Transfer EP/N031431/1 01/02/2018 31/01/2022 £1,212,195
 
Description Protein allostery is essential for fibrous self-assembly, determining a correlation length over which information on the number of concatenated monomers is retained in the fluctuation of the polymer as detected by the end site.

We have identified that the model of 'sticky reptation' explains the rheology of the nascent silk protein solution, and fixes structural parameters difficult to observe otherwise.
Exploitation Route Controlling fibre self assembly both in materials science and in the harmful growth of protein fibrils in the body's cells
Sectors Pharmaceuticals and Medical Biotechnology

 
Description Collaboration with EMBL Hinxton on Allosteric Drugs 
Organisation EMBL European Bioinformatics Institute (EMBL - EBI)
Country United Kingdom 
Sector Academic/University 
PI Contribution Worked through protein structures suggested by the database our partners gave to us
Collaborator Contribution Supply of database of proteins with substrates that might be candidates for allosteric binding without structural change
Impact There have been funding applications to EPSRC (Fellowship) and BBSRC (to be submitted) using input from this funding.
Start Year 2015
 
Description Collaboration with Prof. Amy Shen and Dr. Simon Haward at OIST, Okinawa, Japan 
Organisation Okinawa Institute of Science and Technology
Country Japan 
Sector Academic/University 
PI Contribution Theoretical models of silk fibre formation from silk protein solution in extensional flow; joint application to JSPS/RCUK UK-Japan collaborative grant
Collaborator Contribution Microfluidic experiments on the silk spinning system; joint application to JSPS/RCUK UK-Japan collaborative grant
Impact Grant proposal to RCUK-JSPS pending
Start Year 2018
 
Description PolNet2 
Organisation University of Leeds
Country United Kingdom 
Sector Academic/University 
PI Contribution The network IS a partnership of universities and business in the UK - the coordinating partner administers the activities of the network such as workshops, sandpits and small research projects.
Collaborator Contribution The other member universities contribute co-funding to the workshops that they host, thereby extending the reach of EPSRC funding
Impact The outcomes of these collaborations are multi-disciplinary workshops on topics within the physics of life, outputs are in each case a full report, and increasingly full funding proposals to UK or international funding bodies.
Start Year 2016
 
Description PolNet2 
Organisation University of Surrey
Country United Kingdom 
Sector Academic/University 
PI Contribution The network IS a partnership of universities and business in the UK - the coordinating partner administers the activities of the network such as workshops, sandpits and small research projects.
Collaborator Contribution The other member universities contribute co-funding to the workshops that they host, thereby extending the reach of EPSRC funding
Impact The outcomes of these collaborations are multi-disciplinary workshops on topics within the physics of life, outputs are in each case a full report, and increasingly full funding proposals to UK or international funding bodies.
Start Year 2016