Macromolecular Biochemistry

Research

Research at the Macromolecular Biochemistry group is comprised of the following research themes:

Self-assembly properties and applications of metal-binding peptides and proteins (Aimee Boyle)

It is estimated that approximately 30% of all proteins require a metal to function. Investigating the relationship between metal-binding and peptide/protein folding allows us to uncover fundamental rules for creating metallo-peptides and proteins, which in turn leads to the creation of new structures, potentially with novel functions. Currently, Aimee Boyle focuses on three interrelated research projects with the aim of creating new structures that can fulfil a variety of different applications.
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Chromatin organisation & dynamics (Remus Dame)

The genomic DNA of every organism is organized and compacted in order to fit inside the cell. This is achieved by the joint action of numerous architectural proteins that aid in folding the genome. Genome folding is tightly interconnected with transcription, with genes in certain regions being silenced, while others are highly transcribed. Our interest lies in understanding how architectural proteins act on DNA and how they regulate transcription. We investigate the activity of these proteins in vitro as well as in vivo using biochemical and state-of-the-art biophysical approaches. Read more

Membrane proteins biohybrids (Lars Jeuken)

Membrane proteins reside in the lipid membranes of the cell and are thus amphiphilic, which makes them more difficult to study experimentally. We aim to develop novel biophysical approaches to study membrane proteins and exploit them in biotechnology. In particular, we combine our biological membranes with non-biological materials, creating ‘biohybrids’ with emerging properties that combine the strength of chemistry with that of biotechnology. We characterise these systems using a range of biophysical and bioelectrochemical methods.  As our emphasis is on the development of biohybrids, we have several different lines of research.

In the first line, we aim to couple light-harvesting nanoparticles to membrane proteins for semi-artificial photosynthesis. Artificial photosynthesis aims to produce fuels from solar energy using chemical processes and in semi-artificial photosynthesis, a hybrid approach is taken using both chemical processes and biotechnology. Read more

In a second line of research, we couple lipid membranes and membrane proteins to electrodes for the electrochemical investigation of respiratory-chain enzymes. Using this system, we can study the redox activity of respiratory-chain enzymes electrochemically in a native-like membrane environment and elucidate their interaction with, for instance, natural lipophilic quinones or novel antibiotics. Read more

Finally, we mix biological membranes with amphiphilic block co-polymers to create more robust biomembrane systems. Lipid vesicles (liposomes) are chemically and mechanically fragile and using mixtures with block-copolymers we create biohybrids that are both more robust, but still provide a biofriendly environment to membrane proteins. Read more

Enzyme dynamics and interactions (Marcellus Ubbink)

Enzymes are beautiful catalysts responsible for accelerating and regulating nearly all biochemical reactions. We want to understand how the protein matrix can achieve its function. We aim to decipher the interplay of residues in the active site with the substrate as well as the role of the residues farther away in maintaining the correct structure. In particular, we are interested to understand how dynamics of the protein influence the catalytic process. Substrates must enter and products must leave the enzyme, requiring protein dynamics. Also during the catalysis, conformation changes are important.

One of the enzymes we study is β-lactamase from the bacterium Mycobacterium tuberculosis. It is an excellent model system to study enzyme function as well as protein evolution. We can perform protein evolution readily in the lab, by applying selection pressures in the form of antibiotics and inhibitors on random mutant libraries expressed in E. coli. In this way, we select interesting variants and characterize the enzyme activity, structure and dynamics.

A second line of research is aimed at understanding protein-protein interactions. Weak protein complexes occur very frequently in the cell, e.g. in signalling processes and redox chains. We aim to understand how weak complexes can be formed fast, using encounter states.

We produce the proteins and protein variants in house and characterize them using various biophysical methods, enzyme kinetics, X-ray crystallography, calorimetry and NMR spectroscopy. We develop specific NMR tags for proteins in collaboration with the biosynthetic chemistry group.