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OnderzoekZernike (ZIAM)MIMEC

Biophysics

[Collaborative work of the Onck and Van der Giessen groups]

In this work we study fundamental processes in the cell in order to elucidate the biophysical mechanisms that are responsible for transport of biomolecules through the nuclear pore complex, the transmission of mechanical forces through the cytoskeleton, protein aggregation in neurodegenerative diseases and membrane fusion through conformational dynamics of surface proteins.

1. The Nuclear Pore Complex: gate keepers of the nucleus

Although it has long been assumed that proteins only inherit their function from folding into a specific structure, there is now increasing evidence that intrinsically disordered proteins play an important role in many biological functions, such as nuclear transport. Transport of molecules in and out of the nucleus of eukaryotic cells is controlled by large protein complexes, called ‘nuclear pore complexes’ (NPCs), that are embedded in the nuclear membrane. The actual transport is mediated by intrinsically disordered proteins, FG-nucleoporins (FG-nups), forming a low-density cloud of flexible filaments that line the core region of the NPC. In this project we explore how these FG-nups mediate transport through coarse-grained molecular dynamics simulations.

Nuclear pore complex
Nuclear pore complex

PhD students: A. Mishra, A. Ghavami, H. Jafarinia, H. de Vries

In collaboration with: L. Veenhoff (ERIBA, Groningen) on experimental validation; C. Dekker (Delft University of Technology) on artificial nanopores.

Publications (selection)

2. Biopolymer Networks

Polymer networks are ubiquitous in living matter (e.g., cytoskeleton and extracellular matrix) and are upcoming in the form of engineered fiber networks. Irrespective of their nature, the mechanical properties of these networks depend on the properties of the filament and crosslinks, as well as on the architecture. We use a combination of a FEM designed for filaments and crosslinks along with Monte Carlo techniques to study the elastic and time-dependent properties of these networks.

Biopolymer networks
Biopolymer networks

PhD students: A. Boerma, G. Zagar; Postdoc: T. van Dillen

In collaboration with: S. Papanikolaou (University of West Virginia) for Monte Carlo modeling.

Publications (selection)

  • Zagar, G., Onck, P. R., & van der Giessen, E. (2015). Two Fundamental Mechanisms Govern the Stiffening of Cross-linked Networks . Biophysical Journal , 108 (6), 1470-1479. DOI: 10.1016/j.bpj.2015.02.015
  • Zagar, G., Onck, P. R., & Van der Giessen, E. (2011). Elasticity of Rigidly Cross-Linked Networks of Athermal Filaments . Macromolecules , 44 (17), 7026-7033. DOI: 10.1021/ma201257v
  • Zagar, G., Onck, P. R., & Giessen, E. V. D. (2009). Mechanics of Biophysical Networks with Flexible Cross-links . Biophysical Journal , 96 (3), 122a-123a. DOI: 10.1016/j.bpj.2008.12.544
  • van Dillen, T., Onck, P. R., & Van der Giessen, E. (2008). Models for stiffening in cross-linked biopolymer networks: A comparative study . Journal of the Mechanics and Physics of Solids , 56 (6), 2240-2264. DOI: 10.1016/j.jmps.2008.01.007
  • Huisman, E. M., van Dillen, T., Onck, P. R., & Van der Giessen, E. (2007). Three-dimensional cross-linked F-actin networks: Relation between network architecture and mechanical behavior . Physical Review Letters , 99 (20), [208103]. DOI: 10.1103/PhysRevLett.99.208103
  • Onck, P. R., Koeman, T., Dillen, T. V., & Giessen, E. V. D. (2005). Alternative Explanation of Stiffening in Cross-Linked Semiflexible Networks . Physical Review Letters , 95 (17), [178102]. DOI: 10.1103/PhysRevLett.95.178102

3. Influenza viral fusion

All types of influenza rely on the replication of viruses inside host cells. Replication requires that the virus is able to inject its RNA into the cell, which in turn needs fusion of the viral membrane with the cell membrane. It is known that the protein hemagglutinin acts as a catalyst for this fusion process, but how it does so at the right speed is a long-standing question. Using GROMACS on massively parallel computers, we perform molecular dynamics simulations of hemagglutinin at atomic resolution with the aim to better understand the gymnastics that drive membrane fusion. Identification of a critical step in these conformational changes that is robust for all types of hemagglutinin opens the avenue to a universal physics-based anti-viral drug.

Influenza viral fusion
Influenza viral fusion

PhD student: S. Boonstra

In collaboration with: A.M. van Oijen (University of Wollongong) and PhD student J.S. Blijleven for experimental background and support.

Publications

  • Boonstra, S., Blijleven, J. S., Roos, W. H., Onck, P. R., van der Giessen, E., & van Oijen, A. M. (2018). Hemagglutinin-Mediated Membrane Fusion: A Biophysical Perspective. Annual Review of Biophysics, 47. DOI: 10.1146/annurev-biophys-070317-033018
  • Boonstra, S., Onck, P. R., & Van der Giessen, E. (2017). Computation of Hemagglutinin Free Energy Difference by the Confinement Method. The Journal of Physical Chemistry. B: Materials, Surfaces, Interfaces, & Biophysical, 121(50), 11292-11303. DOI: 10.1021/acs.jpcb.7b09699
  • Blijleven, J. S., Boonstra, S., Onck, P. R., van der Giessen, E., & van Oijen, A. M. (2016). Mechanisms of influenza viral membrane fusion . Seminars in Cell & Developmental Biology . DOI: 10.1016/j.semcdb.2016.07.007
  • Boonstra, S., Onck, P. R., & van der Giessen, E. (2016). CHARMM TIP3P Water Model Suppresses Peptide Folding by Solvating the Unfolded State . The Journal of Physical Chemistry. B: Materials, Surfaces, Interfaces, & Biophysical , 120 (15), 3692-3698. DOI: 10.1021/acs.jpcb.6b01316

4. Protein aggregation in neuro-degenerative diseases

Protein aggregation in neuro-degenerative diseases
Protein aggregation in neuro-degenerative diseases
Most neurodegenerative diseases, such as Alzheimer’s, Parkinson’s and Huntington’s disease, rarely occur at a young age, but its incidence increases dramatically in older people, reaching 10–25% at the age of eighty. These age-related diseases are caused by the aggregation of intrinsically disordered proteins into stable filamentous amyloids that are toxic. The underlying molecular mechanisms of self-assembly and aggregation has been subject of intense debate, but a coherent picture is still lacking. The aim of this project is to identify the specific molecular mechanism behind this protein aggregation, which, if successful, will enhance our understanding of amyloidogenic protein aggregation and might open up new avenues for drug targeting.

PhD student: F. Guo

Last modified:28 May 2018 10.50 a.m.