Conformational dynamics of a nicotinic receptor neurotransmitter binding site

Abstract

Agonists activate receptors by interacting more strongly with active versus resting conformations of their target sites. For each ligand, the strong-weak binding free energy difference sets efficacy and the weak/strong ratio sets efficiency. We performed molecular dynamics simulations to explore the conformational dynamics of a nicotinic receptor neurotransmitter binding site in the weak→strong structural transition. The alternative conformations were identified by comparing calculated and experimental binding free energies for 4 agonists. In weak→strong, the agonist rotates about its cationic center (a ‘flip’), loop C moves in (a ‘flop’) to reposition αY190 to form a water-mediated cross-subunit hydrogen bond with the ligand. The flop restructures the aromatic core, and the flip increases van der Waals interactions to generate a more compact, hydrophobic and stable pocket. The simulations reveal a transient intermediate state as well as changes in a salt bridge that may distinguish agonists.