| Abstract
| - A variety of molecular modeling, molecular docking, and first-principles electronic structurecalculations were performed to study how the α4β2 nicotinic acetylcholine receptor (nAChR) binds withdifferent species of two typical agonists, (S)-(−)-nicotine and (R)-(−)-deschloroepibatidine, each of whichis distinguished by different free bases and protonation states. On the basis of these results, predictionswere made regarding the corresponding microscopic binding free energies. Hydrogen-bonding and cation−πinteractions between the receptor and the respective ligands were found to be the dominant factorsdifferentiating the binding strengths of different microscopic binding species. The calculated results andanalyses demonstrate that, for each agonist, all the species are interchangeable and can quickly achievea thermodynamic equilibrium in solution and at the nAChR binding site. This allows quantitation of theequilibrium concentration distributions of the free ligand species and the corresponding microscopic ligand-receptor binding species, their pH dependence, and their contributions to the phenomenological bindingaffinity. The predicted equilibrium concentration distributions, pKa values, absolute phenomenological bindingaffinities, and their pH dependence are all in good agreement with available experimental data, suggestingthat the computational strategy from the microscopic binding species and affinities to the phenomenologicalbinding affinity is reliable for studying α4β2 nAChR−ligand binding. This should provide valuable informationfor 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 involvingmultiple molecular species of a ligand and in associated rational drug design.
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