It is possible to calculate agonist efficiency from receptor structure.

Abstract

Agonists turn on nicotinic acetylcholine receptors (AChRs) because they bind weakly to resting-C and strongly to active-O conformations of their target sites. Agonist efficiency (η) is the percent of chemical binding energy converted into the mechanical work of C-O gating that depends on the weak/strong binding energy ratio, η=1-ΔΔGC/ΔΔGO. κ has been measured in adult muscle nicotinic AChRs for many agonists and binding site mutations by using electrophysiology. We have compared these experimental values to those calculated from binding free energy estimates to C versus O states at the α-δ binding site. MD simulations were done with an agonist bound to the neurotransmitter site of a muscle AChR (6UVW.pdb). After removing the bound Btx, ligands were docked into the site of the extracellular domain dimer. A five-step equilibration (pre-production) was followed by 200 ns of un-restrained MD simulation using AMBER 2019. The three energy minimas was identified in sequence (m1, m2 and m3) using Principle component analysis (PCA), furthermore their free energies were calculated via MM-PBSA. In general the calculated binding free energy didn’t corroborate well with experimental ones, the calculated binding free energy ratios (η) values for epibatidine, epiboxidine, carbamylcholine and ACh were similar to those estimated by using electophysiology. The results confirm the correctness of our identification of closed-C (m1) versus open-O (m3) binding pocket structures, and suggest that it might be possible in general to calculate agonist efficiency using crystal and MD studies. The structural correlates of agonist efficiency are under investigation.