Conformational dynamics of a nicotinic receptor neurotransmitter binding site

Author:

Singh Mrityunjay1,Indurthi Dinesh C.2,Mittal Lovika1,Auerbach Anthony2,Asthana Shailendra1

Affiliation:

1. Computational Biophysics and CADD Group, Computational and Mathematical Biology Center, Translational Health Science and Technology Institute, NCR Biotech Science Cluster

2. Department of Physiology and Biophysics, University at Buffalo, State University of New York

Abstract

Agonists 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 the Torpedo α–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 calculated in silico with those measured experimentally in 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.

Publisher

eLife Sciences Publications, Ltd

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