[Influence of the orthosteric ligands binding on the conformational dynamics of the B-2-adrenergic receptor by means of essential dynamics sampling simulation]

The influence of binding of the orthosteric ligands on the conformational dynamics of the beta-2-adrenoreceptor was identified using the molecular dynamics method. It was found that there was alittle fraction of the active states of the receptor in its apo (ligand free) ensemble. Analysis of the MD trajectories indicated that such spontaneous activation of the receptor is accompanied by the motion of its VI helix. Thus receptor's constitutive activity is the direct result of its conformational dynamics. On other hand binding of the full agonist resulted in the significant shift of the initial equilibrium towards its active state. Finally binding of the inverse agonist stabilized receptor in its inactive state. Its likely that the binding of the inverse agonists might be the universal way of the constitutive activity inhibition. Our results indicate that ligand binding rather redistribute prexisting conformational degrees of freedom (in accordance to the Monod-Wyman-Changeux-Model) than cause induced fit in it. Therefore ensemble of the biological-relevant receptor conformations have been encoded in its spatial structure and individual conformations from that ensemble might be used by the cell according to the physiological behavior.