Nicotinic acetylcholine receptors (nAChRs) are members of the ligand-gated ion channel superfamily and essential in neurotransmission. A recent experimental study has identified 3 residues (Lys185, Asp187, Ile188) of α6 subunit as determinant of the selectivity on the α-conotoxin BuIA. However, the atomic detail of the structure-function relationship is still elucidated.
In
this research, we have carried out molecular dynamic simulations with
two systems: wild type α4β2 and mutant by 3 residues of α6 subunit
(Tyr185Lys, Thr187Asp, Arg188Ile) with the toxin. The result gave
information that the wild type α4β2 has lost hydrogen bond pair
between Asp199-Arg188, and after mutation the hydrogen bond pair was
replaced by new one between Lys185-Asp187. The average appearance
ratio was 74.82% for Asp199-Arg188 and 32.86% for Lys185-Asp187,
respectively, through the whole simulation time. Thus, loop C of
mutant α4β2 lost rigid form, became more open and flexible form
than the wild type. In the mutant simulation, we also recognized the
reduced distance between toxin and subunits in the binding site that
constructed by the interface between two adjacent subunits: principal
and complementary subunits.
After mutation, the
distance between the center of the toxin and the principal subunit
decreased from 25.32 Å to 23.71 Å, and distance between the center
of toxin and complementary subunits decreased from 16.31 Å to 14.76
Å. These conformational changes have conferred the toxin selectivity
of the α6 subunit.