In the MS-LaserLab / Analytics of Biomolecular Interactions group, we integrate molecular spectroscopy (IR, UV) with (ion mobility) mass spectrometry to understand complex biological processes at the molecular level via characterization of molecular structure, intra/inter-molecular interactions and structural changes.
Aggregation in neurodegenerative diseases
Our goal is to understand the early stages of the aggregation mechanism of neurodegenerative diseases such as Parkinson’s disease, as these still soluable early formed olgimers are seen as the most toxic. Therefore, we will determine the structure and structural changes of key aggregation intermediates, which lie on the on- and off-pathways towards fibril formation. By comparning pathogenic and functional aggregating peptide (segments) and proteins, structural similarities and differences will be mapped leading to a structural understanding of aggregation toxicity.
Studying the aggregation kinetics: To elucidate the evolution of the elusive early stages in peptide self-assembly of functional and pathological aggregation, we will develop and use droplet-microfluidics ESI-sources. This will help us to study: (i) the formation of aggregates in an aqueous, controlled environment, (ii) to select a specific time-point on the aggregation curve, and (iii) ideally to follow nucleation events.
We are developing, in collaboration with MS Vision, an experimental 4-dimensional IR-MS based methodology, which measures the temporal evolution, size, shape and structure, to probe structure and kinetics in one single experiment. This will be achieved by the novel combination of droplet-based microfluidics electrospray ionization and ion mobility mass spectrometry with IR ion spectroscopy.
At this moment, the IM-MS optimized for spectroscopy has been designed at MS Vision and ready to be developed. In the mean time, droplet-microfluidics with push and pull ESI sources and optical ion trap for UV experiments are being developed in the lab at the VU.
Directing & controlling the aggregation process: The gained insights on the aggregation mechanism will be used to examine inhibitors on specific key oligomeric states. We will examine the effect of known inhibitor-candidates on key intermediates and spur the development of the next generation inhibitors. In collaboration with dr. Samantha Hughes (VU, Environment&Health), we have positively explored the use of C. elegans to pre-examine inhibitor-candidates. Successful inhibitor-candidates will be applied to specific aggregate intermediates found in our studies.
Glycoscience in neurological develoment and disease (lead by Dr. Melissa Baerenfaenger): After several advances in the fields of genomics and proteomics, our understanding about the glycome or glycoproteome is vastly lacking behind. This is especially true for the role of glycosylation in the central nervous system and its function in neurological development and disease, where the occurrence and function of structurally unique “brain-type” glycans is still unexplained. We want to decipher the structural heterogeneity of glycosylation in the central nervous system and its alteration in neurological diseases of aging. By using mass spectrometry with integrated ion mobility and spectroscopy, we investigate how altered glycosylation influences protein structure and function to understand disease mechanisms.
Previous Research: Functional Aggregation (partly continued at VU Amsterdam)
The self-assembly of peptides can also be functional nature, both biological (hormone storage) or for the development of smart biomaterials, where self-assembly is used to design specific materials. The differences in chemical, biological and physical properties of the peptides result in a range of different nanostructures, such as nanotubes, nanospheres, nanorods and nanoplates. Our aim is to elucidate how the molecular structure of isolated clusters of peptides can be related to their nanostructure.
Past Research (FELIX, Radboud University): Far-IR Spectroscopy & Astrochemistry (continued by dr. Lemmens)
Mass- and conformer selective far-IR and THz spectroscopy has proven to be an excellent approach to obtain structural information on peptides ranging from single amino acids to large peptides and peptide clusters. In our studies, we focus on the synergy between far-IR spectroscopy and theory, and how this can provide an unprecedented picture on the structure of peptide aggregates formed on the fly (i.e. in the gas phase).
Interstellar space is far from empty; it houses a wealth of (organic) components that end up in stars and planets, such as the earth. Despite the signs that a significant part of carbon in interstellar clouds is expected to be locked up in polycyclic aromatic hydrocarbons (PAHs), little of their presence and formation is known. Their infrared signatures from interstellar space were already detected decades ago, but until now, not a single PAH has been identified yet. In the laboratory, we investigate the infrared characteristics of PAHs to supprt their identiffication and theoretical models. We also aim to reveal new pathways of their formation in interstellar conditions. Ultimately resulting in the understanding of the origin of our organic building blocks.