<br/>The alpha7 nicotinic acetylcholine receptors (CHRNA7) are ligand-gated ion channels widely expressed in the central nervous system and involved in neurocognitive functions including memory. CHRNA7 receptors are homopentamers, with the orthosteric binding site located at the interface between N-terminal extracellular domains of two consecutive subunits. Humans uniquely express a variant of CHRNA7 called CHRFAM7A, which is a partial duplicate of the “canonical” CHRNA7, lacking a part of the N-terminal ligand-binding domain. Even though CHRFAM7A expression has been associated with a number of neuropsychiatric disorders including schizophrenia and Alzheimer’s disease, the effects of CHRFAM7A expression on ligand binding remains largely unknown.<br/>In the present study, we have modelled N-terminal domains of nicotinic receptor pentamers containing CHRFAM7A subunits and their molecular dynamics have been subsequently investigated at the atomistic level of detail. Molecular Dynamics (MD) simulations were carried out on sub-microseconds time scales using the AMBER-99SB-ILDN force field and TiP3P water model to study the pentamers containing different CHRNA7/CHRFAM7A ratio. The binding sites amenable for binding of small molecule ligands were mapped using established FTMap solvent mapping technique.<br/>Our results showed that two chimeric CHRFAM7A subunits are preferentially located consecutively within the pentamer. The CHRFAM7A dimer with adjacent CHRNA7 trimer was the most stable isoform of nicotinic alpha7 receptors containing CHRFAM7A. FTMap analysis revealed that the putative allosteric binding sites are located at the interface of two CHRFAM7A subunits and at CHRNA7/CHRFAM7A interface. Unexpectedly, the orthosteric binding site at the distal CHRNA7 site was negatively affected by the presence of CHRFAM7A dimer within the receptor. Unique allosteric site was detected at CHRFAM7A, and synthetically feasible small molecule hits were discovered by the virtual screening of a focused small molecular library, followed by the atomistic MD simulation. Our results explain why disease-linked CHRFAM7A receptors are unlikely to respond to orthosteric CHRNA7 ligands, and indicate that despite this lack of sensitivity, CHRFAM7A receptors may be effectively targeted by allosteric modulators.<br/>

Conformational analysis and small molecule ligand recognition of the human-specific CHRFAM7A nicotinic receptor implicated in neuropsychiatric disorders

2019 Fall National Meeting

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