We have used molecular dynamics simulations to study the interaction between cyclic peptides and the neuropeptide Y Y4 receptor (Y4R), which belongs to the Class A GPCRs.  These peptides bind Y4R with picomolar affinity (Figure 1) and exhibit a considerably more pronounced Y4R selectivity compared to previous ligands. Therefore, they represent promising leads the development of drug-like Y4R ligands.
Receptor-catalyzed G protein activation
Our work is focused on the analysis of the formation of a productive complex of active receptor and G protein. Productive means that the receptor is observed catalyzing the nucleotide exchange in the G protein. In our unbiased all-atom MD simulations, the uncoupled receptor and GDP-bound inactive G protein spontaneously form a complex. Long-range allosteric effects are observed from the active receptor to the nucleotide, opening the nucleotide-binding pocket and breaking half of the GDP contacts. In subsequent umbrella sampling MD simulations, we observed the release of GDP from its binding pocket without touching the GDP. Our simulations provide insights into the structural mechanism the universal process of receptor-catalyzed G protein activation (see Figure 2 below).
Ongoing Research / Outlook
As in previous funding periods, project pr94su has made significant advances in the field of GPCR simulations, both in terms of developing computational protocols and in contributing to mechanistic and structural GPCR research in general. In the latter respect, the project has once more underlined the unusual importance in this experimentally very challenging field.
Our studies of the activation of GPCRs have reached a stage at which we now have a powerful tool for studying the activation/deactivation process in atomistic detail and can proceed to production simulations designed to answer open mechanistic questions. Future work will concentrate on the role of the pre-active conformation first revealed in atomistic detail in reference  and now routinely identifiable for class A GPCRs, and on the roles and conformational effects of different kinds of ligands, with special emphasis on allosteric modulators.
Our close connection with Research Training Center 1910 Medicinal Chemistry of selective GPCR ligands provides us with unique opportunities to extend the scope and conclusions of experimental studies by considering new ligand/receptor combinations for which unpublished experimental data are available. In this respect, our studies on receptor-ligand interactions contribute new fundamental knowledge to enhance the ligand-design process. Protocols developed together with Prof. Francesco Gervasio (Geneva) allow us to translate the simulation results into analyses familiar to experimental GPCR researchers.
Finally, our studies go one step further than analyzing the differently active conformations of the receptor itself to investigate the process by which the active conformation(s) of the receptor actually lead to signaling via G-protein activation. These studies represent a significant advance in the scope and applicability of GPCR simulations