Research Activities

Last updated 01/2023

Antibodies have emerged as a major class of biopharmaceuticals, with indications ranging from autoimmune diseases to cancer. A majority of antibody-related research is currently based on sequence information or stationary structures alone. Here in Innsbruck, we apply a wide range of simulation-based techniques to link structural and dynamic information to pharmaceutically relevant properties such as specificity, stability, hydrophobicity and developability. A key topic of our research is the accurate representation of antibodies as conformational ensembles. Our scope is to provide state-of-the-art tools to develop and optimize novel antibody therapeutics.
It is still entirely unclear what makes a protein an allergen. However, what we do know so far is, that a key step in allergic sensitization is the cleavage of allergen proteins into small peptides. Yet, most protease cleavage sites are found within secondary structure elements, which are not accessible to proteases. The allergen thus has to undergo major conformational rearrangements and local unfolding to become susceptible to proteolysis. This process is strongly linked to a decreasing pH value in the endosome. Using classical and enhanced MD simulations, we study these partial unfolding and refolding events and profile their relation to proteolytic susceptibility. Furthermore, we apply constant pH MD simulations coupled with dynamic NMR experiments to capture shifts in unfolding probability upon changes in pH. Embedded in a strong network of experimental collaborators, we work on elucidating the molecular origins of protein stability, allergenic potency and allergen cross-reactivity.
Ion Channels
Voltage-gated calcium channels control most activity-dependent functions of excitable cells, like synaptic transmission in neurons and the contraction of heart and skeletal muscles. To accomplish such diverse functions, different calcium channels activate at different voltages and with distinct kinetics. Voltage-dependent activation of the channel upon membrane depolarization is determined by four distinct repeats, consisting of voltage-sensing domains (VSD I-IV) and pore-domains (PD I-IV) forming the common channel pore. We investigate structural determinants of voltage-gating properties in different calcium channel isoforms to elucidate the role of different VSDs in channel gating. Particularly, we also want to provide mechanistic explanations for distinct disease variants on a molecular level.

Vibrational Spectroscopy

To investigate and subsequently overcome the major challenges in earth’s climate change, it is crucial to probe the molecular composition of earth’s atmosphere. Molecules in the atmosphere are commonly characterized by infrared spectroscopy where molecular vibration is measured. However, to achieve a reliable characterization of experimentally measured spectra, calculation of molecular vibration (beyond the harmonic approximation) is mandatory. In recent years, solving the time-independent nuclear Schrödinger equation to calculate molecular vibration has been significantly improved. In that context, we collaborate with experimentalists and theoreticians to establish physicochemical justifications for spectra of atmospherically relevant molecules, such as water, carbon dioxide, methane, etc. We aim on promoting both, the development of computational methods and the improvement of experimental interpretation.

The human genome comprises more than 560 different proteases, suggesting that nearly 3% of all human genes code for proteases. Their vast variety of biological functions stretch from the degradation of proteins in the digestive tract, over key aspects in the immune system, to involvement in blood coagulation. Depending on its task, substrate recognition of a protease thus needs to range from highly specific to widely promiscuous. We investigate the underlying physical mechanisms on the protein-protein interface, which influence the binding process and determine substrate recognition. We employ and develop MD-based tools to quantify and localize the individual terms contributing to specificity or promiscuity in biomolecular recognition.