title: In silico point mutation and evolutionary trace analysis applied to nicotinic acetylcholine receptors in deciphering ligand-binding surfaces.
abstract: The nicotinic acetylcholine receptors (nAChRs) are members of the Cys-loop superfamily and contain ligand gated ion channels (LGIC). These receptors are located mostly in the central nervous system (CNS) and peripheral nervous system (PNS). nAChRs reside at pre-synaptic regions to mediate acetylcholine neurotransmission and in the post synaptic membrane to propagate nerve impulses through neurons via acetylcholine. Malfunction of this neurotransmitter receptor is believed to cause various neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease and schizophrenia, and nAChRs are thus important drug targets. In the present work, starting from an earlier model of pentameric alpha7nAChR, a considerable effort has been taken to investigate interaction with ligands by performing docking studies with a diverse array of agonists and antagonists. Analysis of these docking complexes reveals identification of possible ligand-interacting residues. Some of these residues, e.g. Ser34, Gln55, Ser146, and Tyr166, which are evolutionarily conserved, were specifically subjected to virtual mutations based on their amino acid properties and found to be highly sensitive in the presence of antagonists by docking. Further, the study was extended using evolutionary trace analysis, revealing conserved and class-specific residues close to the putative ligand-binding site, further supporting the results of docking experiments.
authors.affiliation: Department of Bioinformatics, Bioinformatics Centre and Computational Biology Laboratory, Bharathiar University, Coimbatore, 641064, India.
authors.forename: Marimuthu
authors.initials: M
authors.lastname: Parthiban
authors.forename: Piramanayagam
authors.initials: P
authors.lastname: Shanmughavel
authors.forename: Ramanathan
authors.initials: R
authors.lastname: Sowdhamini
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D019295:Computational Biology; D017124:Conserved Sequence; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010802:Phylogeny; D017354:Point Mutation; D017434:Protein Structure, Tertiary; D011978:Receptors, Nicotinic / Q000737:chemistry* / Q000235:genetics; D020539:Sequence Analysis, Protein
chemical_list: D008024:Ligands; D011978:Receptors, Nicotinic