Ligand induced change of β2 adrenergic receptor from active to inactive conformation and its implication for the closed/open state of the water channel: insight from molecular dynamics simulation, free energy calculation and Markov state model analysis

The reported crystal structures of beta(2) adrenergic receptor (beta(2)AR) reveal that the open and closed states of the water channel are correlated with the inactive and active conformations of beta(2)AR. However, more details about the process by which the water channel states are affected by the active to inactive conformational change of beta(2)AR remain illusive. In this work, molecular dynamics simulations are performed to study the dynamical inactive and active conformational change of beta(2)AR induced by inverse agonist ICI 118,551. Markov state model analysis and free energy calculation are employed to explore the open and close states of the water channel. The simulation results show that inverse agonist ICI 118,551 can induce water channel opening during the conformational transition of beta(2)AR. Markov state model (MSM) analysis proves that the energy contour can be divided into seven states. States S1, S2 and S5, which represent the active conformation of beta(2)AR, show that the water channel is in the closed state, while states S4 and S6, which correspond to the intermediate state conformation of beta(2)AR, indicate the water channel opens gradually. State S7, which represents the inactive structure of beta(2)AR, corresponds to the full open state of the water channel. The opening mechanism of the water channel is involved in the ligand-induced conformational change of beta(2)AR. These results can provide useful information for understanding the opening mechanism of the water channel and will be useful for the rational design of potent inverse agonists of beta(2)AR.