Investigation of the beta-amyloid binding interface with a candidate marker for neurodegenerative diseases

Neurodegenerative diseases represent a group of slowly progressive, hereditary or acquired pathologies of the nervous system. Their common feature is neurodegeneration, which leads to various neurological symptoms, including dementia, movement disorders, cognitive impairment, and behavioral changes. Due to the increasing prevalence of neurodegenerative diseases in modern society, there is a growing number of studies focused on exploring the molecular mechanisms underlying these diseases, which opens prospects for developing new approaches for early diagnosis and effective treatment methods. The biomolecules associated with the pathogenesis of neurodegenerative diseases include the acetylcholine receptor and beta-amyloid. A modified form of the HAEE tetrapeptide (His-Ala-Glu-Glu), which likely binds to beta-amyloid in the presence of cations, appears promising for investigation. Using molecular modeling methods, complexes of the acetylcholine receptor with beta-amyloid, as well as the modified form of HAEE tetrapeptide with beta-amyloid, were obtained both in the presence and absence of zinc cation. Mapping and characterization of binding interfaces in the modeled complexes were performed, along with comparative analysis of complex stability using molecular dynamics methods. It was demonstrated that the presence of zinc ions leads to the stabilization of two types of complexes. The nicotinic acetylcholine receptor- beta-amyloid complex in the presence of zinc showed the highest stability compared to other studied complexes. The HAEE tetrapeptide-beta-amyloid complex exhibited the lowest stability in the experiments. Phylogenetic analysis of the origin of the 18-amino acid residue long N-terminal $\alpha$-helix sequence of human nAChR containing the tetrapeptide HAEE revealed highly homologous orthologous proteins with similar biological function in the majority of the most abundant animal classes.