Distinct conformational dynamics of the type-2 Angiotensin II receptor bound to Angiotensin II and Angiotensin (1–7)

Abstract

Abstract The Angiotensin II type-2 receptor (AGTR2) is a G protein-coupled receptor (GPCR) that mediates vasodilatory, anti-proliferative, and cardioprotective responses as part of the renin–angiotensin system (RAS). However, the precise structural dynamics underlying its ligand-specific activation remain incompletely understood. In this study, we performed long-timescale molecular dynamics (MD) simulations to investigate how Angiotensin peptides differentially modulate the structural dynamics of AGTR2 in both inactive- and active-like conformations and to elucidate ligand-specific modulation of AGTR2 in the RAS protective arm. Ang II stabilized a ‘Locked Active State’ through compact TM3–TM6 distances, persistent hydrogen bonding (PHE8–LYS215 5.42 ), salt bridges (ARG2-ASP279 6.58 , ARG2-ASP297 7.32 ), hydrophobic contacts (TRP100 2.60 , MET128 3.36 ), and rotameric locking of micro-switches. These interactions stabilized Helix 8, enhancing dynamic network connectivity and supporting ligand-dependent activation-related conformational tendencies rather than a full canonical GPCR activation transition. Conversely, Ang1–7 induced a ‘Flexible Intermediate State’ characterized by weaker interactions (PRO7–THR125 3.33 ), dynamic instability at the Helix 8 interface, and increased conformational sampling. Activation motif analyses (CWxP, PIF, E/DRY, NPxxY), DCC maps, CP, DRIN metrics, and PCA confirmed distinct signaling features for each ligand. This study provides a dual functional profile for AGTR2, where Ang II acts as a strong conformational stabilizer promoting activation-related dynamic features, while Ang 1–7 serves as a dynamic modulator. These findings contribute to a structural and dynamic framework for understanding AGTR2 signaling and supporting its therapeutic potential in fine-tuning cardiovascular responses within the RAS.