Modeling Multiple Species of Nicotine and Deschloroepibatidine Interacting with α4β2 Nicotinic Acetylcholine Receptor: From Microscopic Binding to Phenomenological Binding Affinity

Content Provider	Scilit
Author	Huang, Xiaoqin Zheng, Fang Crooks, Peter A. Dwoskin, Linda P. Zhan, Chang-Guo
Copyright Year	2005
Abstract	A variety of molecular modeling, molecular docking, and first-principles electronic structure calculations were performed to study how the α4β2 nicotinic acetylcholine receptor (nAChR) binds with different species of two typical agonists, (S)-(−)-nicotine and (R)-(−)-deschloroepibatidine, each of which is distinguished by different free bases and protonation states. On the basis of these results, predictions were made regarding the corresponding microscopic binding free energies. Hydrogen-bonding and cation−π interactions between the receptor and the respective ligands were found to be the dominant factors differentiating the binding strengths of different microscopic binding species. The calculated results and analyses demonstrate that, for each agonist, all the species are interchangeable and can quickly achieve a thermodynamic equilibrium in solution and at the nAChR binding site. This allows quantitation of the equilibrium concentration distributions of the free ligand species and the corresponding microscopic ligand-receptor binding species, their pH dependence, and their contributions to the phenomenological binding affinity. The predicted equilibrium concentration distributions, $pK_{a}$ values, absolute phenomenological binding affinities, and their pH dependence are all in good agreement with available experimental data, suggesting that the computational strategy from the microscopic binding species and affinities to the phenomenological binding affinity is reliable for studying α4β2 nAChR−ligand binding. This should provide valuable information for future rational design of drugs targeting nAChRs. The general strategy of the “from-microscopic-to-phenomenological” approach for studying interactions of α4β2 nAChRs with (S)-(−)-nicotine and (R)-(−)-deschloroepibatidine may also be useful in studying other types of ligand−protein interactions involving multiple molecular species of a ligand and in associated rational drug design.
Related Links	http://europepmc.org/articles/pmc3182463?pdf=render https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3182463/pdf
Ending Page	14414
Page Count	14
Starting Page	14401
ISSN	00027863
e-ISSN	15205126
DOI	10.1021/ja052681+
Journal	Journal of the American Chemical Society
Issue Number	41
Volume Number	127
Language	English
Publisher	American Chemical Society (ACS)
Publisher Date	2005-09-27
Access Restriction	Open
Subject Keyword	Journal: Journal of the American Chemical Society Biochemistry and Molecular Biology Studying Α4β2 Microscopic Binding Phenomenological Binding Affinity
Content Type	Text
Resource Type	Article
Subject	Chemistry Colloid and Surface Chemistry Biochemistry Catalysis