Openings

PhD or Postdoc position on Multiscale modelling of aggregation of intrinsically-disordered proteins in health and disease.

There is a vacancy for a PhD student or postdoc on coarse-grained molecular dynamics of intrinsically disordered proteins. For further questions please contact prof. dr. ir. Patrick Onck or prof.dr.ir. Erik van der Giessen.

Description:

Proteins are long polymer chains consisting of twenty different amino-acids. Their sequence determines in what ordered structures the proteins fold. It has long been thought that proteins need structure to perform their function, but compelling evidence has appeared in the last decade showing that also intrinsically-disordered proteins (IDPs, proteins whose sequence is such that they do not fold) play a key role in many biological functions. Examples of such IDPs are the FG-Nups that mediate transport through the nuclear pore complex and RNA-binding proteins (RBPs) that drive the formation of biological condensates. To describe these biological processes, we developed a coarse-grained (CG) molecular dynamics (MD) model that is fine enough to account for the exact amino-acid sequence (the molecular grammar that dictates the secondary structure) but that is also coarse enough to describe their collective behavior in large supramolecular assemblies. 

The disordered nature of IDPs also comes at a risk. The exposedness of the amino-acids and their dynamic nature also enhances the propensity of the IDPs to phase separate and aggregate in large, ordered protein fibrils. This has been observed for a wide range of different IDPs, such as FG-Nups, RBPs and disease-related IDPs that cause neurodegenerative diseases (e.g., ALS, Parkinson’s, Alzheimer’s and Huntington’s disease). This aggregation process has generic components but, intriguingly, the specific fiber architecture depends strongly on the amino-acid sequence of the underlying IDP. 

The aim of this work is to unravel the fundamental mechanisms that dictate the multiscale self-assembly process from individual IDPs into amyloid fibers and how this depends on the amino-acid sequence of the IDP. We have recently extended our CG MD model with the ability to form hydrogen bonds based on both experimental and lower-scale atomistic MD data. The model has been specifically parametrized with respect to FG-Nups and the polyQ protein (responsible for Huntington’s disease) and within this PhD project we will extend its applicability to other IDPs as well. Such a versatile, experimentally calibrated CG MD model currently does not exist and we believe that its successful application to different IDPs does not only yield new fundamental insights on sequence-dependent disorder-to-order transitions in IDP-systems, it might also open new therapeutic avenues in the combat of neurodegenerative disorders. 

The project will be carried out in close collaboration with groups at the UMCG and with colleagues at the ZIAM working on neurodegenerative diseases.