A Computational Analysis of the Factors Governing the Dynamics of α7 nAChR and Its Homologs

Abstract

The a7 nicotinic acetylcholine receptor is a homopentameric ion channel from the Cys-loop receptor superfamily targeted for psychiatric indications and inflammatory pain. Molecular dynamics studies of the receptor have focused on residue mobility and global conformational changes to address receptor function. However, a comparative analysis of a7 with its homologs that cannot trigger channel opening has not been made so far. To identify the residues involved in a7 activation, we ran triplicate 500-ns molecular dynamics simulations with an a7 extracellular domain homology model and two acetylcholine-binding protein homologs. We tested the effect of ligand binding and amino acid sequence on the structure and dynamics of the three proteins. We found that mobile regions identified based on root mean-square deviation and root mean-square fluctuation values are not always consistent among the individual a7 extracellular domain simulations. Comparison of the replica-average properties of the three proteins based on dynamic cross-correlation maps showed that ligand binding affects the coupling between the C-loop and the Cys-loop, vestibular loop, and b1-b2 loops. In addition, the main-immunogenic-region-like domain of a7 went through correlated motions with multiple domains of the receptor. These correlated motions were absent or diminished in a7 homologs, suggesting a unique role in a7 activation.