PhD Scientific Days 2024

Poster Session A - Molecular Medicine 1.

AT1R Ligand Binding Simulation 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. A ꞵ-arrestin-biased peptide has been shown to decrease blood pressure while increasing cardiac function in a rat model. Although the same peptide did not improve clinical outcomes in a 30 day trial, the long term use of non-peptide ꞵ-arrestin-biased ligand could provide therapeutic benefits.
Aims: Therefore we set out to develop such ligands by developing a model which would help us in understanding the binding mode of non-peptide agonists and aid the virtual screening by calculating binding energies.
Methods: We used well-tempered metadynamics with funnel restraints. The main collective variable (CV) was the distance between the alpha carbon atom of the conserved TRP6.48 and the center of mass of the ligand. We tested several other CVs to facilitate ligand binding.
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. Furthermore, we identified the transition at ARG167 residue as a slow mode, and used a torsion CV describing the ligand orientation to facilitate the transition.
Funding: Hungarian National Research, Development, and Innovation Fund (NKFI FK 138862, K 139231, and K 134357). Competitive Central Hungary Operational Programme VEKOP-2.3.2-16-2016-00002. János Bolyai Research Scholarship and János Bolyai Research Scholarship Plus of the Hungarian Academy of Sciences BO/00807/21. Gedeon Richter Talentum Foundation in the framework of Gedeon Richter Excellence PhD Scholarship of Gedeon Richter.