Studies of the Activation Steps Concurrent to Ligand Binding in δOR and κOR Opioid Receptors Based on Molecular Dynamics Simulations

ABSTRACT

Although agonists and antagonists occupy the same space in opioid receptors the agonists only are able to evoke their activation and different agonists may lead to different conformational states of the receptor. Agonist binding is the first step in ligand-induced receptor activation which proceeds through series of conformational changes. To investigate the relationship between the final movements of a ligand in a receptor binding site and the first steps of the activation process in δOR and κOR opioid receptors we chose a set of rigid ligands with the structural motif of tyramine. On the basis of conducted molecular dynamics simulations we propose that, similarly as in the case of µOR [Kolinski and Filipek, TOSBJ 2008], agonists and antagonists bind to Y3.33 but only agonists are able to move deeper into the receptor binding site and to reach H6.52. The movement from Y3.33 to H6.52 induces breaking of the TM3-TM7 connection (“3-7 lock”). However, conversely to morphine (previous paper) butorphanol did not induce breaking of this connection in a single movement but instead a time of about 20 ns was required and this process was composed of a series of separation and joining events. We also observed a concerted motion of W6.48 and H6.52 suggesting existence of an extended “rotamer toggle switch”. Simultaneous action of both switches, the “3-7 lock” and the “rotamer toggle switch”, implies a temporal but also spatial (an agonist linking H6.52 and D3.32) dependence between them.

Keywords:

Molecular dynamics, homology modeling, hydrophobic interactions, G protein coupled receptors, opioid receptors, molecular switches..