prof. dr. P.C.A. van der Wel
Solid-state NMR spectroscopy
We use and develop multidimensional solid-state NMR methods to probe the molecelular structure and dynamics of large, often insoluble, macromolecular assemblies. On the one hand, we design and implement techniques that measure the geometry of molecules in atomic-resolution detail. Crucially, our ssNMR methods can be deployed to determine detailed structural features even in context of samples that lack overall (crystalline) order. As such, we provide atomic-resolution structural information in filamentous hydrogels, protein aggregates and other types of nanomolecular assemblies. On the other hand, we also study samples featuring dynamic and static disorder that implies the absence of a single well-defined structure, where we use NMR methods to describe the structural ensemble of conformational states.
Structure-function studies via ssNMR: A central goal in our ssNMR studies is not to determine structure for its own sake, but rather to use our methods to disentangle how structure (and dynamics!) dictate and enable functional properties of biological as well as human-made assemblies. The ability of ssNMR to probe dynamics (in the form of relaxation measurements as well as order parameters) is often of particular importance, given that functional processes often require particular types of dynamics.
Amyloidogenic self-assembly in human disease
One recurring theme in our work relates to the ability of many polypeptides (proteins) to form filamentous structures based on long intermolecular β-sheets. This principle gained notoriety in context of Alzheimer's disease, but (remarkably) similarly underpins many other neurodegenerative diseases. Since 2010, we have been using ssNMR (and other methods) to illuminate the misfolding and aggregation behaviour of expanded polyglutamine proteins involved in Huntington's disease (HD) and related disorders. Our combination of tailored structural and dynamic measurements to contribute various new mechanistic and structural findings to the field of HD research. We are continuing work in this area, by increasingly integrating our detailed structural measurements with correlated functional and mechanistic assays probing the very processes involved in disease causation in HD and beyond.
Amyloidogenic processes in the design of functional bio-/nano-materials.
The properties of amyloid-like filamentous materials are increasingly recognized for their potential in the design of self-assembling human-made materials with a wide range of functional properties. In these design processes, the mechanistic principles of amyloidogenesis are both leveraged and can also become better understood. In particular, so-called primary and secondary nucleation events appear to play critical roles in the templated self-assembly, both in biology and in the design of amyloid-based materials. Solid-state NMR studies and mechanistic/kinetics assays are used to dissect the structure-function relationship and how these find their origins in the self-assembly pathway itself.
Protein-lipid interactions & membrane structure.
Two-dimensional liquid-crystalline membranes are sites of critical function as well as dysfunction in biology and human disease. We employ solid-state NMR spectroscopy to dissect the dynamic interactions that underpin various membrane-associated processes. Particular topics of interest include the role of non-bilayer phases and membrane curvature in biology, the molecular recognition events that facilitate the trafficking and targeting of membrane-binding proteins and the role of chemical modification (e.g. peroxidation) of lipids in biology. For example, we have been probing the early stages of mitochondrial apoptosis, where all these processes play a direct role.
For more informatie visit also our research group website.
|Last modified:||06 April 2020 4.52 p.m.|