Molecular Modeling of G Protein-Coupled Receptors

Binding model of PAR1 tethered peptide agonist. (A) MD simulation snapshot of PAR1 in a POPC bilayer. The tethered ligand is shown in red. (B) Close-up view of the tethered ligand binding pose.

G protein-coupled receptors (GPCRs) are the largest group of membrane receptors and mediate the physiological responses to a wide range of stimuli such as hormones, neurotransmitters, and light. Upon activation by ligand binding, GPCRs undergo conformational changes, leading to the activation of intracellular signaling pathways via heterotrimeric G proteins or arrestins. Because of their involvement in many diseases, GPCRs are important drug targets and about 50% of drugs on the market target GPCRs.
Proteinase-activated receptors (PARs) are GPCRs that are characterized by a special activation mechanism. While most GPCRs are activated by the association of soluble small molecules or peptides, activation of PARs involves cleavage of the receptor N terminus by proteases, exposing a tethered peptide ligand that interacts with the receptor binding pocket. Among the four PARs, PAR1 is an important regulator of hemostasis and thrombosis and a therapeutic target for the prevention of cardiovascular diseases.
In our research group we study the question how different tethered peptide ligands of PAR1 generated by thrombin or activated protein C (aPC) trigger different G protein or arrestin-mediated signaling pathways. Molecular modeling and molecular dynamics simulations are used to predict the binding mode of thrombin- and aPC-generated peptides and elucidate the atomic details of the PAR1 activation mechanism and its changes induced by different ligands. We also investigate the binding mode and molecular mode of action of parmodulins, small biased ligands, which inhibit coagulation via PAR1 but maintain the cytoprotective effects of PAR1. In order to guide our computational simulations, data from different experimental methods are collected, including non-canonical amino acid crosslinking and site-directed mutagenesis, which are performed in collaborations.

Energy landscape of PAR1 conformations during receptor activation. The energy landscape was calculated using the string method with swarms of trajectories. Conformational changes triggered during the activation process are marked along the string and in the shown on the right side.

Selected Publications:

  • Künze G, Isermann B. Targeting biased signaling by PAR1: function and molecular mechanism of parmodulins. Blood. 2023. 141(22):2675-2684. doi: 10.1182/blood.2023019775
  • Liessmann F, Künze G, Meiler J. Improving the Modeling of Extracellular Ligand Binding Pockets in RosettaGPCR for Conformational Selection. Int J Mol Sci. 2023. 24(9):7788. doi: 10.3390/ijms24097788
  • Joedicke L, Mao J, Kuenze G, Reinhart C, Kalavacherla T, Jonker HRA, Richter C, Schwalbe H, Meiler J, Preu J, Michel H, Glaubitz C. The molecular basis of subtype selectivity of human kinin G-protein-coupled receptors. Nat Chem Biol. 2018. 14(3):284-290. doi: 10.1038/nchembio.2551

Collaborations:

Prof. Dr. Berend Isermann, Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital Leipzig, University of Leipzig