Conformational dynamics of a nicotinic receptor neurotransmitter binding site

Agonists increase receptor activity by providing net-favorable binding energy to active versus resting conformations of their target sites. We used molecular dynamics (MD) simulations to explore dynamics of the low-to-high affinity conformational change (L[->]H) at the Torpedo -{delta} nicotinic acetylcholine receptor neurotransmitter site, using 4 agonists. Alternative conformations were identified in trajectories generated from a single starting structure by matching approximate binding energies calculated in silico with exact values measured experimentally in vitro. In all simulations, the L[->]H transition started with a rotation of the agonist about its cationic center (flip), followed by a staged downward displacement of loop C (flop) and the formation of a compact, hydrophobic and stable high-affinity pocket (fix). Agonist rotation and a transient intermediate state are only in simulations but can be confirmed or refuted, for example by time-resolved structures.