Abstract
In this study, by homology modelling and molecular dynamics (MD) simulation, models of l-stepholidine (l-SPD) activating the 5-HT1A and D1 receptors were constructed. In 100-ns MD simulations, the D1 and 5-HT1A receptors were activated by the partial agonist l-SPD, conforming with the global toggle switch activation model and the sequential activation model. The residues Y7.53 and Y5.58 swing significantly between different transmembrane (TM) domains after activation. Similarities between D1 and 5-HT1A included (1) the outward motion of TM-5; (2) the ionic lock was independent of the tilt of TM-6 and (3) there was an apparent bending of TM-6, and the ring of l-SPD formed strong π–π interactions with residue W6.48. Differences between the two included the following: (1) in 5-HT1A, l-SPD formed a hydrogen bond with Ala1725.46 of TM-5, and the intracellular end of TM-5 moved outward slowly; that hydrogen bond did not form with the D1 receptor; (2) l-SPD formed stronger interactions with D3.32 and W6.48 in the D1 receptor than in the 5-HT1A receptor and (3) the hydrogen bonding network was somewhat different in SPD-5-HT1A and SPD-D1 receptors. We propose the interaction between l-SPD and D3.32 or/and W6.48 is the original driving force during the whole activation process.