Abstract
Dopamine receptors (DRs), key members of the G protein-coupled receptor family, regulate critical neurological functions and are implicated in disorders such as Parkinson's disease and schizophrenia. Recently, the resolved DR-G protein complexes have provided important structural insights. Microswitches, local structural motifs, are known to play a significant role in their activation. However, the dynamic activation of microswitches by partial agonists and dual-functional ligands, as well as the influence of subtype-specific allostery on signaling pathway selection, remain unresolved. In this study, molecular dynamics simulations are employed to investigate the structural dynamics and activation mechanisms of D1DR and D2DR in complexes with their cognate G-proteins and various ligands. Particular focus is given to the dual-functional flavonoid kurarinone, a prenylated compound from Sophora flavescens roots that acts as a D1DR antagonist and D2DR agonist. The simulations show that full agonists activate all microswitches, with tyrosine toggles interacting with internal water molecules to stabilize the activated conformation and propagate signals to distal residues. Crucially, this activation may facilitate the entry of internal water molecules, leading to the formation of a continuous water channel. Our analysis suggests that this water network acts as a functional bridge, linking the orthosteric binding pocket to the G-protein interface to relay allosteric signals. In contrast, partial agonists and antagonists display distinct regulatory mechanisms that limit structural rearrangements. These findings provide atomic-level insights into water-mediated DR activation dynamics and ligand-specific signaling pathways, offering valuable perspectives for the rational design of subtype-selective drugs.