PhD Scientific Days 2023

Molecular Sciences - Posters K

AT1R Ligand Binding Mechanism Characterization With Well-Tempered Metadynamics

Text of the abstract

Introduction: The angiotensin II type 1 receptor (AT1R) has a major role in the renin-angiotensin system, and is known to exhibit biased signaling. However, its ligand binding mechanism is not fully understood. The existing metadynamics binding protocols for seven-transmembrane receptors proved to be ineffective in the case of AT1R.
Aims: Therefore we set out to develop a metadynamics protocol to model the binding of ligands from the solvent to the orthosteric binding pocket of AT1R.
Methods: We used well-tempered metadynamics with two collective variables (CVs): The distance between the alpha carbon atom of the conserved Trp6.48 and the center of mass of the ligand. A coordination CV that measures the strength of the contact of the AT1R N-terminal to the second extracellular loop (ECL2).
Results: Our results indicate that the N-terminal can unbind from the groove of ECL2, this allows access to the orthosteric binding pocket from the extracellular side. After the binding of Angiotensin II (Ang II) the N-terminal "closes down" the binding pocket, and the N-terminal - ECL2 interaction is stabilized by Ang II. In the case of angiotensin receptor blockers binding this interaction is not stabilized by the ligand.
Conclusion: The N-terminal of the AT1R acts as a "lid" for the orthosteric binding pocket and can sterically block the binding/unbinding of the ligands. Our results can aid the development of new AT1R ligands.
Funding: FK 138862, K 139231. The scientific work/research and/or results publicised in this article was reached with the sponsorship of Gedeon Richter Talentum Foundation in framework of Gedeon Richter Excellence PhD Scholarship of Gedeon Richter.