PhD Scientific Days 2023

Molecular Sciences - Posters K

AT1R Ligand Binding Mechanism Characterization With Well-Tempered Metadynamics

Előadó neve

Dr. Ádám, Misák

Neptun code

NHVSC6

Előadó munkahelye

Department of Physiology, Semmelweis University, 1094 Budapest, Hungary

Előadó telefonszáma

+36308297793

Előadó e-mail címe

misak.adam@stud.semmelweis.hu

Az előadás címe

AT1R Ligand Binding Mechanism Characterization With Well-Tempered Metadynamics

Szerző(k) neve és munkahelye

Ádám Misák1, András Dávid Tóth1,2,4, Miklós Cserző1,3, László Hunyady1,2,3, Gábor Turu1,2
1 Department of Physiology, Semmelweis University, 1094 Budapest, Hungary.
2 ELKH-SE Laboratory of Molecular Physiology, Eötvös Loránd Research Network and Semmelweis University, 1085 Budapest, Hungary.
3 Research Center for Natural Sciences, Institute of Enzymology, 1117 Budapest, Hungary.
4 Department of Internal Medicine and Haematology, Semmelweis University, 1088 Budapest, Hungary.

Bemutatás módja

Poszter

Szekció

Molecular Sciences - Posters K

Language of the presentation

English

Preferred session

Molecular Sciences

Összefoglaló szövege

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.

University and Doctoral School

Semmelweis University, Doctoral School of Molecular Medicine

Supervisor

Dr. Turu Gábor

Publication of my abstract

I give consent to the publication of my abstract on the website of the congress.

Kind

Szabad

Status

elfogadva

Accepted presentation method

poszter

Előadás fájl jóváhagyás

nem rendelkezett róla

Előadó

7428

Start

11:12

End

11:17

Authors (legacy)

Ádám Misák1, András Dávid Tóth1,2,4, Miklós Cserző1,3, László Hunyady1,2,3, Gábor Turu1,2
1 Department of Physiology, Semmelweis University, 1094 Budapest, Hungary.
2 ELKH-SE Laboratory of Molecular Physiology, Eötvös Loránd Research Network and Semmelweis University, 1085 Budapest, Hungary.
3 Research Center for Natural Sciences, Institute of Enzymology, 1117 Budapest, Hungary.
4 Department of Internal Medicine and Haematology, Semmelweis University, 1088 Budapest, Hungary.