Conformational dynamics of a nicotinic receptor neurotransmitter binding site

Abstract

AbstractAgonists turn on receptors because they provide net favorable binding energy to active versus resting conformations of their target sites. We used simulations to explore conformational dynamics of the weak→strong binding transition at theTorpedoα–δ nicotinic acetylcholine receptor orthosteric site. Using 4 agonists, the alternative site conformations were identified in trajectories generated from a single starting structure by matching binding energies calculatedin silicowith those measured experimentallyin vitro. The weak→strong transition starts with a rotation of the agonist about its cationic center (‘flip’), followed by a downward displacement of loop C that repositions αY190 (‘flop’), followed by formation of H-bonds between the ligand, a structural water and the δ subunit loop E backbone (‘fix’). The result is a compact, hydrophobic and stable pocket with higher affinity for agonists. The simulations reveal a transient intermediate state in the weak→strong transition.