Comparative and statistical analysis of nAChR sequences: An ab initio approach to the origin of molecular discrimination

Compared with traditional structure-based approaches for the identification of species-specific ligands, the ab initio approach, based on large-scale protein sequences from different species, has been used to locate specific sites that may be important to the molecular selectivity of species. Statistically significant differences in the distribution of residues in different species and differences in the physicochemical properties of residue-specific sites may largely account for species selectivity. The nicotinic acetylcholine receptor (nAChR), an important neuro-receptor with significantly different ligand selectivity in different species, was used to test our method. Because of the lack of nAChR structural information, the mechanism of ligand discrimination is unclear which hinders attempts at novel molecular design. In this study, the specific site residues 186 and 189 in the principal subunits and residues 34, 55, 56, 57, 106 and 112 in complementary subunits of nAChR were identified by applying our method with stringent statistical cutoffs. These sites were predicted to contribute to ligand selectivity and this result coincides well with the known experimental data.