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

Lead Research Organisation: Durham University
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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Davenport F (2022) Physics of Brains in iScience

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Dresser L (2022) Tween-20 Induces the Structural Remodeling of Single Lipid Vesicles. in The journal of physical chemistry letters

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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

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 29/04/2023 £1,212,195
 
Description The earliest phase of the fellowship resulted in one collaborative paper already with the two post doctoral fellows. It shows that the coarse-grained 'allosteron' model for a single fluctuating thermal mode in a protein or protein sub-unit is effective in predicting behaviour in multimers though self-assembly. there are three classes: (i) rings; (ii) chains; (iii) random but tuned aggregating families.

In the second year we have discovered that there is an application of the allosteric fluctuation mechanism to the self-assembly of virus capsids. Since then we have identified the subtle mechanism by which fluctuation allostery causes negative co-operativity to arise.

We have also worked with experimental colleagues in Sheffield on silk protein solution and found that the 'sticky reptation' mechanism explains the linear rheology of this material, deriving structural and physical parameters from the model fits in agreement with molecular data. We have since then also found the underlying molecular mechanisms by which silk protein solutions flows in the duct of silk-worms. Both polymer entanglement and charged attraction are important. We have constructed a theoretical physics model that explains it quantitatively.

In the latter part of the fellowship, very significant progress has been made on the objectives.

In the case of the biological physics of silk formation, there has been rather a breakthrough. We have successfully extended the 'sticky reptation' rhea-physics model for silk to fully non-linear flows in shear and also extension. Doing so has unearthed completely new and surprising physics: the combination of flow and temporary associations of the sole protein polymers results in a power-law scaling stretch distribution in extensional flows, in which a family of driven critical points is controlled by flow rate as well as the internal physics parameters of the silk polymers. The underlying physics was published in a Physical Review Letter. Several other publications have been also forthcoming. The planned evolutionary strand makes contact with this work through the discovery of convergent evolution of the regular charged groups along all species of silk protein. Furthermore, combining this emergent critical behaviour with a nucleation model for the fibres explains for the first time how it is that natural silk solution spinning is so much more energy efficient than with human made fibres. The steady sate result as recently been extended to fully transient flows, as in reality. Laplace Transform methods assist numerical computations in pinning down the dynamics, which displays clear optima to evolution.

The project has given rise to the team editing a special edition of J Roy Soc INTERFACE on biophysical rheology for 2023.

In the protein allostery part of the project, extensive calculations have now been performed one four important proteins (two associated with the SARS-COV-2 protein). This has enabled a full methdological survey of the ENM method, which will appear in an invited article for a special edition on protein allostery of the Journal of Molecular Biology.

The evolution strand has made contact with the work of Ard Louis in Oxford and Sebastian Ahnert in Cambridge, and a paper on the explicit mapping of GP maps with fitness landscapes is in preparation.
Exploitation Route The paper suggests further experiments and calculations. It also moves towards the new design of allosteric drugs
The work on silk should inform the molecular design of non-oil-based polymer fibres
Sectors Manufacturing, including Industrial Biotechology

URL https://www.york.ac.uk/news-and-events/news/2021/research/computer-modelling-covid/
 
Description These are early days, but a conversation has begun with pharmaceutical company UCB on using our ideas in new pathways to allosteric drugs. The work on silk has been reported to a consortium of manufacturers interested in routes towards sustainable non-oil based plastics.
First Year Of Impact 2019
Sector Pharmaceuticals and Medical Biotechnology
Impact Types Economic

 
Title Lattice modelling software fore coarse-grained self-assembly 
Description Lattce-polymer brownian simulation code specifically designed for monte-carol studies of polymer self-assembly. Specific geometric rules and inter-particle potentials can be applied to any, and any pair of interactions between different species of monomer. 
Type Of Technology Software 
Year Produced 2019 
Impact Initial results are promising for modelling self-assembly of biopolymers