title: A new role for the nonpathogenic nonsynonymous single-nucleotide polymorphisms of acetylcholinesterase in the treatment of Alzheimer's disease: a computational study.
abstract: Single-nucleotide polymorphisms (SNPs) are implicated in the complexity of understanding the genetics of diseases and their therapeutics. Here we have attempted to determine the impact of nonsynonymous SNPs (nsSNPs) on structure, dynamics, and ligand-binding properties of the human acetylcholinesterase (hAChE) protein, which has been targeted in the treatment of Alzheimer's disease. Of the reported 153 SNPs, 4 nsSNPs, namely, A415G, P104A, V302E, and Y119H, were prioritized to be functionally unfavorable by SIFT and PolyPhen algorithms. Molecular dynamics simulation revealed these nsSNP forms to be structurally stable, and they are also considered functionally active as they lie away from the catalytic triad. However, the aromatic amino acids lining the active-site gorge exhibited altered degrees of side chain dihedral angles. Such conformational alterations were evaluated for their ability to interfere with binding of hAChE inhibitors. The inhibitors (donepezil, galantamine, rivastigmine, and tacrine) were oriented differently in comparison to the native because of the steric hindrance offered by the altered dihedral angles. Interestingly, huperzine A alone exhibited higher efficiency in its binding to the AChE and retained similar orientation irrespective of the polymorphisms since the orientation of Asp74 involved in its binding and trafficking remained unaltered in all protein forms. Therefore, we conclude that nsSNPs confer changes to the dynamicity of proteins, which in turn affects their ligand-binding properties rather than their stability. Considering the diverse polymorphic nature of hAChE, while contemplating any structure-based drug design, the common, nonpathogenic nsSNPs should be considered for the utmost efficacy of drugs.
authors.affiliation: Department of Biotechnology, School of Biotechnology and Genetic Engineering, Bharathiar University , Coimbatore, Tamil Nadu, India .
authors.forename: Ponne
authors.initials: P
authors.lastname: Saravanaraman
authors.forename: Raj Kumar
authors.initials: RK
authors.lastname: Chinnadurai
authors.forename: Rathanam
authors.initials: R
authors.lastname: Boopathy
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D000544:Alzheimer Disease / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics; D000595:Amino Acid Sequence; D002800:Cholinesterase Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D020641:Polymorphism, Single Nucleotide; D011485:Protein Binding; D011487:Protein Conformation; D016415:Sequence Alignment
chemical_list: D002800:Cholinesterase Inhibitors; D000110:Acetylcholinesterase
keywords: Alzheimer's disease; acetylcholinesterase; dihedral angle; molecular dynamics; nonsynonymous single-nucleotide polymorphism