Protein-ligand and protein-protein interactions play an important role for the function of living organisms. Thus, one of the research areas of our group is focused on analyzing regions of binding interactions. In particular, we apply our computational tools and expertise to investigate ligand binding sites and protein-protein interfaces to understand the interaction of binding partners and to identify possibilities to modulate such interactions.
A long-standing development in our groups is the characterization of binding pockets using knowledge-based potentials [4,23]. The family of DrugScore pair-potentials has been successfully used to describe binding sites between small molecules and proteins [14,31], small molecules and RNA  and protein-protein interactions [104,107]. Currently, we are seeking to update and improve these knowledge-based functions by exploiting the ever-growing Protein Data Bank. Furthermore, we develop and utilize state-of-the-art modelling and simulations techniques, including enhanced sampling methods and free energy calculations, to understand the conformational interplay between binding partners as well as the associated energetics [18,26,73,81,85,157]. Our investigation of the per-residue decomposition of binding energetics represents a methodological hallmark [16,98]. We actively extend these approaches towards an application to membrane-bound systems . The integration of such simulations with experimental data allows the elucidation of interactions with atomistic accuracy that agree with in vitro time scales [139,162]. Next to analysis of known binding epitopes, we investigated possibilities to identify transient binding pockets ; a topic, which is currently revisited.
We have successfully studied a number of highly relevant targets, in close collaboration with experimentalists. RUNX1/ETO is an oncogene, required for the onset and maintenance of acute myeloid leukemia (AML). We were able to identify small molecule inhibitors that supress the RUNX1/ETO tetramerization via the NHR2 domain by mimicking α-helical structures  and targeting hotspot residues . Our lead compound significantly reduced dissemination of leukemic cells in mice and increased the survival rate . Another validated target for cancer treatment is HSP90. We modelled the dimeric structure, studied binding site hotspots, and investigated the behavior of inhibitory peptides by homology modelling and MD simulations [104,127]. ETR1 is a prototype of plant ethylene receptors, which promotes fruit ripening. The control of fruit ripening has an enormous economic potential. By combining homology modelling, free ligand diffusion MD simulations, and rigidity theory with experimental site-directed mutagenesis, we deduced the site and potential mode of action of ripening inhibitory peptides on ETR1. NsrR is a response regulator involved in resistance to the lantibiotic nisin. By using structural modelling, we shed light on the DNA-binding interface of NsrR . PEPC, phosphoenolpyruvate carboxylase, plays a central role in carbon fixation in C4 plants, which use a more effective photosynthetic pathway than C3 plants. Selective inhibitors of PEPC in C4 plants are promising starting points of herbicide development. Using docking and shape-based virtual screening, we were able to identify new classes of potential C4 plant herbicides [134,154].
An emerging target for the modulation of protein-protein interactions are dimerization interfaces of GPCRs. The homo- and heterodimerization of GPCRs has been shown to influence the membrane trafficking, signaling, and degradation of these proteins. Furthermore, agonistic and antagonistic signals can be transferred from one receptor in a heterodimer to the other. This opens up new possibilities to influence the behavior and signaling of GPCRs by targeting their dimerization epitope. In order to employ knowledge-driven approaches, however, the dimerization epitopes of the GPCR of interest have to be discerned. We unraveled the dimerization interfaces of TGR5 in live cells in an integrated modeling approach combining modeling, molecular dynamics simulations and FRET. Here, we modeled TGR5 on GPCR dimers known from X-ray crystal structures and combined them with an exhaustive conformational ensemble of an attached fluorophore and its linker. We used this to compare the expected FRET distance distributions to the ones measured in live cells and could, thus, show that TGR5 adopts a dimerization epitope involving transmembrane helix 1 and helix 8 .