Addiction to nicotine, and possibly other tobacco constituents, is a major factor that contributes to the difficulties smokers face when attempting to quit smoking. Amongst the various subtypes of nicotinic acetylcholine receptors (nAChRs), the α4b2 subtype plays an important role in mediating the addiction process. The characterization of human α4b2-ligand binding interactions provides a molecular framework for understanding ligand-receptor interactions, rendering insights into mechanisms of nicotine addiction and may furnish a tool for efficiently identifying ligands that can bind the nicotine receptor. To date, a human structure of the nAChR α4b2 has not been elucidated. Therefore, we conducted clustering analysis on the ligand binding pockets of 27 complexes of α4b2 bound with ligands including nicotine in the PDB (Protein Data Bank) and observed two distinct groups of protein conformations. One representative complex was selected from each of the two groups (4AFH and 2BYR) as the templates to construct homology models. The initial 3D structures from homology modeling were optimized through 100 nanoseconds (ns) molecular dynamics (MD) simulations. Comparison of the optimized structures with their initial structures indicated that the MD simulations led to relatively larger changes in the conformation of the loops while the helixes had very small changes in the optimizations. The Ramachandran plots of the optimized 3D structures showed that &gt;99% of residues were placed in the allowed zone, indicating the optimized 3D structure is in a higher quality. The root-mean squared divations (RMSD) plots from the resultant trajectories showed that the structures achieved a steady state after ~20 ns simulation with a stable fluctuation of approximately 3Å. The refined structures of human α4b2 will be used to develop a model for screening the &gt;8000 tobacco constituents to identify ones that may have human α4b2 nAChR binding activity.<br/>Disclaimer: The findings and conclusions in this abstract are not a formal dissemination of information by the US Food and Drug Administration (FDA) and do not represent Agency position or policy.

Three dimensional structures of human nicotinic acetylcholine receptor α4b2 constructed through homology modelling and molecular dynamics simulation

255th National Meeting (2018)

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