Multiscale Simulations of Droplet-Membrane Mutual Remodelling

Eukaryotic cells contain a large number of compartments within the cytosol. Organelles are membrane-bound compartments and cellular droplets are sub-compartments with liquid-like properties. Key to this project are recent observations that cellular droplets interact with membranes, which leads to mutual remodelling of their morphologies. For instance, during autophagy, membrane sheets enwrap harmful cytosolic droplets to degrade them finally. With increasing number of cellular processes now known to exploit these novel droplet-membrane interactions, it is our aim in this project to develop a much-needed understanding of such phenomena using a multiscale simulation approach, combining Molecular Dynamics and membrane elasticity theory.

Research Project

Phase separation is a familiar concept in the physical sciences, ranging from the common observation of water and oil demixing, to its use to create advanced materials for food, energy and photonic applications. In cellular biology, intracellular phase separation has garnered much attention recently as a means to organise intracellular solutions through the formation of droplet-like sub-compartments. Examples of such droplet compartments include the stress granules and P-bodies.

Key to this project is that these droplets interact with membranes, and as a result, the droplets and the membranes can mutually remodel their shapes and morphologies. For example, during autophagy, membrane sheets remodel into double-membrane organelles called autophagosomes. Autophagosomes can selectively isolate cargoes for elimination, including harmful cytosolic droplets. In fact, numerous physiological processes have been identified with similar membrane morphologies, suggesting that these droplet-membrane interactions are a general cellular mechanism.

The aim of this interdisciplinary project is to develop the much-needed understanding of these droplet-membrane interactions, and their mutual remodelling during droplet isolation. Here, we will use a multiscale modelling approach. At the molecular level, we will employ molecular dynamics simulations to study the formation of the droplets via a liquid-liquid phase separation mechanism and the affinity between the droplet and membrane. These results will inform a continuum modelling approach based on elasticity theory for studying the droplet and membrane shapes. The theoretical/computational work by the student will also provide an important framework to rationalise and guide ongoing in vitro and in vivo experiments.

Our long-term goal is two-fold. First, we propose that elasto-capillary interaction – the interplay between the surface tension of cytosolic droplets and the deformability of lipid membranes – is an important but overlooked generic physical mechanism in cells. Second, we will provide new insights into autophagy and other cellular processes with similar membrane morphologies. An important question is whether disrupted elasto-capillary interaction can lead to various diseases such cancer and neurodegenerative disorders.

Training & Skills

The student will work at an exciting interface between physics, chemistry and biology, and will be rigorously trained in computational biophysics methods, covering both atomistic molecular dynamics simulations and continuum modelling methods. The student will have access to High Performance Computing facilities at Durham and Newcastle.

The student will also collaborate and interact actively with the experimental partners in Germany. Furthermore, to achieve our long-term strategic vision, our groups have developed a broad network of collaborators in Japan, Norway, Germany, France, UK and USA. The student will have access to this network.

The successful candidate will have an excellent first degree (first or upper second class or equivalent) in theoretical physics or related subjects, e.g. biophysics, computational chemistry, computational biology, etc. They will demonstrate skills in mathematical modelling and computer simulations. Scripting and programming skills would be advantageous.

Further Information

Dr Halim Kusumaatmaja
[Email Address Removed]
+44 191 334 3627

How to Apply

To apply for this project please visit the Durham University application portal to be found at: https://www.dur.ac.uk/study/pg/apply/

Please select the course code F1A201 for a PhD in Molecular Sciences for Medicine and indicate the reference MoSMed20-13 in the ‘Field of Study’ section of the application form.

Should you have any queries regarding the application process at Durham University please contact the Durham MoSMed CDT Manager, Emma Worden at: [Email Address Removed]