Computational investigation of mechanistic insights of Aβ42 interactions against extracellular domain of nAChRα7 in Alzheimer’s disease

Abstract

Aim: Amyloid beta (Ab) 1-42, which is a basic constituent of amyloid plaques, binds with extracellular transmembrane receptor nicotine acetylcholine receptor a7 (nAChRa7) in Alzheimer's disease. Materials and Methods: In the current study, a computational approach was employed to explore the active binding sites of nAChRa7 through Ab 1-42 interactions and their involvement in the activation of downstream signalling pathways. Sequential and structural analyses were performed on the extracellular part of nAChRa7 to identify its core active binding site. Results: Results showed that a conserved residual pattern and well superimposed structures were observed in all nAChRs proteins. Molecular docking servers were used to predict the common interactive residues in nAChRa7 and Ab1-42 proteins. The docking profile results showed some common interactive residues such as Glu22, Ala42 and Trp171 may consider as the active key player in the activation of downstream signalling pathways. Moreover, the signal communication and receiving efficacy of best-docked complexes was checked through DynOmic online server. Furthermore, the results from molecular dynamic simulation experiment showed the stability of nAChRa7. The generated root mean square deviations and fluctuations (RMSD/F), solvent accessible surface area (SASA) and radius of gyration (Rg) graphs of nAChRa7 also showed its backbone stability and compactness, respectively. Conclusion: Taken together, our predicted results intimated the structural insight on the molecular interactions of beta amyloid protein involved in the activation of nAChRa7 receptor. In future, a better understanding of nAChRa7 and their interconnected proteins signalling cascade may be consider as target to cure Alzheimer's disease.

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