Soiree

Liquid-liquid phase separation in cells

Spatial control of irreversible protein aggregation

Dr Christoph Weber

Max Planck Institute, Dresden

 

Fluid-like genome organization through multiscale molecular modelling

Dr Rosana Collepardo

Maxwell Centre, University of Cambridge

Thursday 28th March 2019
Time: 4pm
Venue: Room G20, Royal School of Mines, Imperial College London
Contact: Ms Hafiza Bibi
Tel: 020 7594 7252

Spatial control of irreversible protein aggregation

Dr Christoph Weber

Liquid cellular compartments spatially segregate from the cytoplasm and can regulate aberrant protein aggregation, a process linked to several medical conditions, including Alzheimer's and Parkinson's diseases. Yet the mechanisms by which these droplet-like compartments affect protein aggregation remain unknown. Here, we combine kinetic theory of protein aggregation and liquid-liquid phase separation to study the spatial control of irreversible protein aggregation in the presence of liquid compartments. We find that, even for weak interactions between the compartment constituents and the aggregating monomers, aggregates are strongly enriched inside the liquid compartment relative to the surrounding cytoplasm. We show that this enrichment is caused by a positive feedback mechanism of aggregate nucleation and growth which is mediated by a flux maintaining the phase equilibrium between the compartment and the cytoplasm. Our model predicts that the compartment volume that maximizes aggregate enrichment in the compartment is determined by the reaction orders of aggregate nucleation. The underlying mechanism of aggregate enrichment could be used to confine cytotoxic protein aggregates inside droplet-like compartments suggesting potential new avenues against aberrant protein aggregation. Our findings could also represent a common mechanism for the spatial control of irreversible chemical reactions in general.

Biography: Christoph A. Weber (Max Planck Institute for the Physics of Complex Systems) studied physics at the Ludwig Maximilian university in Munich and completed his PhD in the group of Erwin Frey about actively propelled particle systems. Then he joined the Max Planck Institute for the Physics of Complex Systems in Dresden as a postdoc and worked together with Frank Jülicher and Anthony Hyman on the physics underlying the spatial-temporal organization of non-membrane bound organelles. Then he investigated active poroelastic materials and the kinetics of protein aggregation in the group of L. Mahadevan at Harvard University. In 2018, he returned back to Dresden as a research group leader joining the Max Planck Institute for the Physics of Complex Systems and the Center for Systems Biology. His group “Mesoscopic Physics of Life” is interested in non-equilibrium phase transitions in living systems, aims to understand the biological function of protein aggregates and protein phases in cells, and how a minimal set of inanimate molecules could have formed life-like assemblies at the origin of life.

 

Fluid-like genome organization through multiscale molecular modelling

Dr Rosana Collepardo

The three-dimensional organisation of the DNA is one of the great marvels of physical biology. By winding around a special class of proteins, the metre-long DNA manages to compress enormously to fit inside tiny (6 μm) nuclei, avoid entanglement and, moreover, maintain exquisite control over the accessibility of the information it carries. The structure of this remarkable complex of DNA and proteins, known as chromatin, determines how easily the DNA can be accessed and, thus, it is intimately linked to gene expression regulation. In this talk, I will explain how the structure of chromatin is much more fluid and tuneable than originally proposed, which explains how chromatin achieves various different roles in vivo according to the transcriptional state, cell-cycle stage, or in response to environmental signals  (Collepardo and Schlick, PNAS 2014). I will also discuss how multiscale modelling can be used to reveal the molecular mechanisms behind epigenetic control of chromatin structure and provide a link between epigenomes, structure, and gene function (Collepardo et al., JACS, 2015). Finally, I will talk about the “new phase” of genome organization: a new paradigm that suggests how liquid-liquid phase separation of genomic mixtures might help organize genomic information into distinct membrane-less compartments inside the Cell nucleus.

Short bio: Rosana Collepardo is a junior group leader (Winton Advanced Research Fellow) at the Department of Physics, University of Cambridge. Her work focuses on developing theoretical and computational methods to elucidate the physical mechanisms that determine packaging of DNA inside cells. She did her DPhil with David Manolopoulos at the PTCL in Oxford, and trained as a postdoc with Daan Frenkel and David Wales at the University of Cambridge, Modesto Orozco at the Barcelona Supercomputing Centre, and Tamar Schlick at New York University. Her group has recently been awarded an ERC starting grant to investigate genome organization with sub-nucleosome resolution.

 

6yBGvF_web.jpg

Follow @tyc_london for updates from the Thomas Young Centre.