Aggregation and self-assembly in colloidal and biological systems

Lead Research Organisation: University of Cambridge
Department Name: Chemistry

Abstract

Nature has been ingenious in devising materials and devices to have specialised properties and to perform specific tasks in living matter. Not only must molecular building blocks be synthesised, they must also adopt the correct conformations and assemble themselves into functioning superstructures. At the same time, they must avoid interfering with all the other organisational processes occurring within the same space.Many tasks in living cells are performed by proteins. These molecules are chains of amino acids that fold into intricate structures dedicated to their particular function. Determining the structure is an important stage in unravelling a protein's function, and this is most often achieved by x-ray crystallography. To obtain a useful resolution it is necessary to purify the protein and grow defect-free crystals up to almost millimetre size. However, proteins have evolved to be difficult to crystallise, since aggregation of that sort would be deleterious to their function. Indeed, diseases like that of haemoglobin C arise from unwanted crystallisation. Accordingly, searching for physical conditions where adequate crystals can be grown is a difficult and time-consuming task.An important factor affecting the tendency of proteins to crystallise is the directionality of their interactions with each other due to the non-uniformity of their surfaces. Very little is known about the influence of directionality on crystallisation, and a major aim of the research proposed here is to investigate the effects using computer simulation. Although computer power continues to increase apace, it is nowhere near sufficient to treat an atom-by-atom representation of protein crystallisation. Instead of such a brute-force approach, we must devise coarse-grained models that embody the essential physics of protein interactions, and analyse them with sophisticated tools. In addition to being computationally tractable, these models have the advantage of revealing general underlying principles rather than case-specific answers.Proteins often organise themselves into discrete superstructures in order to accomplish a task. An elegant but pernicious example is the self-assembly of capsids, the coats of viruses that encapsulate their genetic material. About half of all viruses are roughly spherical (in fact, icosahedral) in shape, and are efficiently built from copies of a small number of proteins. The fact that many capsids can assemble reliably from their isolated subunits is remarkable and not easy to explain in detail. In particular, the ability to avoid construction errors and to form complete shells in favour of many partial fragments is poorly understood. Here again, simplified computer models can assist by elucidating possible pathways and the underlying thermodynamics of self-assembly. This knowledge could inspire antiviral therapy targeted at the assembly stage, rather than at infection itself. It could also be turned to positive uses by designing tiny containers to administer drugs.The coarse-grained modelling of biological molecules springs from techniques developed for colloid science. Colloids cover a broad range of dispersed nanoscale particles and everyday examples are as diverse as cream, ink and fog. In many human-made colloids, it is possible to exert fine control over the properties of the particles, thereby influencing their collective behaviour. Further projects in this proposal take up the idea of colloids as ``designer atoms.'' For example, how can rod-like molecules be encouraged to connect at low densities to make light-weight electrically conducting materials? What happens to colloidal gels and glassy materials if they are composed of mixtures of sizes and interactions rather than a uniform component? Computer simulations have a vital role to play in answering these questions.

Publications

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Batista VM (2010) Crystallization of deformable spherical colloids. in Physical review letters

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Blaak R (2007) Reversible gelation and dynamical arrest of dipolar colloids in Europhysics Letters (EPL)

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Fantoni R (2007) Patchy sticky hard spheres: analytical study and Monte Carlo simulations. in The Journal of chemical physics

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Hansen-Goos H (2012) Density functional theory for Baxter's sticky hard spheres in confinement. in Physical review letters

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Miller M (2008) Structural trends in clusters of quadrupolar spheres in Molecular Physics

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Miller MA (2010) Topological characteristics of model gels. in Journal of physics. Condensed matter : an Institute of Physics journal

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Miller MA (2009) Dynamical arrest in low density dipolar colloidal gels. in The Journal of chemical physics

 
Description The way that molecular building blocks aggregate or assemble into larger structures is crucial in determining the physical properties of the resulting material. Evolution has been ingenious in devising building blocks that assemble into complexes and materials to perform specific tasks in living matter. By different means, human beings can also manipulate particles to control the way that they organise themselves in artificial materials. This research programme has been concerned with using computer simulation to understand self organisation and how that understanding can be exploited to design particles that will self-assemble in a chosen way.

Many tasks in living cells are performed by proteins: chains of amino acids that fold into structures dedicated to their function. One strand of research in this programme involved characterising a simple computational model of proteins. Coarse-grained models are both computationally more tractable and better reveal underlying principles than a full atomistic description. We showed that a stripped-down representation of proteins as flexible tubes with directional hydrogen bonding and variable hydrophobicity captures many of the essential features of real proteins. Importantly, the model allowed us to study the competition between different protein structures and to show when they are most vulnerable to incorrect (and potentially pathological) folding.

Lattice models, where connected beads on a cubic grid represent the chain of amino acids, can also capture the essential physics of proteins. We have used such a model to study the way that proteins fold into their final structure, how this folding can be induced by interaction with a specific target substrate, and how the whole folding and binding process can be influenced by the presence of competing interactions from other molecules. In particular, inert polymers grafted around a protein's binding target can selectively tune both the barrier and the binding affinity of the protein.

An even more coarse-grained approach is needed to look at how proteins order into crystals. Crystal samples are needed to unravel protein structure from x-ray crystallography, but most proteins resist crystallisation, since that would be deleterious to their biological function in living matter. Folded proteins are compact, rather impenetrable objects. However, they are not rigid. We have devised a model of hard but deformable particles to investigate the effect of flexibility on crystallisation. Our phase diagram shows that flexibility moves crystallisation to higher densities, but also allows particles to pack more efficiently. The next stage will be to see how this affects the thermodynamic barriers to crystallisation.

Also included in this research programme were studies of composite materials of colloidal particles. One example is the structure of light-weight electrically conducting materials composed of a connected network of highly elongated conductors, such as carbon nanotubes, suspended in an insulating matrix. The nanotubes can be encouraged to connect up by introducing an additional component into the suspension to act as depletion agents. Our simulations probed the effect of depletion attraction in detail, showing that competing trends are at play and that the interpretation of some recent experiments may need to be revisited for a full understanding. Another major piece of work looked at the low-density networks formed by dipolar particles. Such particles readily form chains that can branch to create a gel-like structure and can become dynamically arrested at sufficiently low temperature. While investigating the dynamic properties of gels we also developed new ways of quantifying the topology of low-density networks.
Exploitation Route The simplified models devised and characterised in this work predict various effects that can be tested experimentally and exploited both to gain a deeper understanding of the basic science and, ultimately, to develop useful materials and prevent disease. For example, the work on electrically conducting networks of nanorods sheds light on how light-weight conducting materials behave, while the work on simple protein models allows competition between biologically functioning and pathologically misfolded proteins to be understood at a general level.
Sectors Chemicals,Pharmaceuticals and Medical Biotechnology

 
Description British Council Alliance Scheme
Amount £2,500 (GBP)
Organisation British Council 
Sector Charity/Non Profit
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 01/2009 
End 12/2010
 
Description EPSRC Programme Grant
Amount £2,741,015 (GBP)
Funding ID EP/I001352/1 
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Academic/University
Country United Kingdom of Great Britain & Northern Ireland (UK)
Start 10/2010 
End 09/2015