분자동역학 전산모사에 의한 α6 nAChR Subunit의 α-conotoxin BuIA에 대한 선택성 연구
Selectivity of the α6 nAChR Subunit on α-conotoxin BuIA Studied by Molecular Dynamics Simulations
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Nicotinic acetylcholine receptors (nAChRs) are essential for neurotransmission and important therapeutic targets of diseases related to neurotransmission. A recent experimental study identified three residues (Lys185, Asp187, and Ile188) of the α6 nAChR subunit as determinants of α-conotoxin BuIA selectivity, yet how these residues confer toxin selectivity remains unclear. In this study, we performed all-atom molecular dynamics simulations with two toxin-bound α4β2 nAChR systems: the wild-type α4β2 and one in which we replaced the three α4 subunit residues with three α6 subunit residues identified in an experimental study (Tyr185Lys, Thr187Asp, and Arg188Ile). After mutation, Asp199 lost the salt bridge formed with Arg188 in the wild type located around loop C. Then, the loop C conformation changed and became more flexible than that of the wild type. We also detected reduced space between the toxin and the binding site in the mutant simulation, resulting in increased binding affinity to the toxin. Therefore, we propose a new Asp199 mutation that breaks the salt bridge and may produce similar selectivity to that of the Arg188 mutation.
Abstract
Nicotinic acetylcholine receptors (nAChRs) are essential for neurotransmission and important therapeutic targets of diseases related to neurotransmission. A recent experimental study identified three residues (Lys185, Asp187, and Ile188) of the α6 nAChR subunit as determinants of α-conotoxin BuIA selectivity, yet how these residues confer toxin selectivity remains unclear. In this study, we performed all-atom molecular dynamics simulations with two toxin-bound α4β2 nAChR systems: the wild-type α4β2 and one in which we replaced the three α4 subunit residues with three α6 subunit residues identified in an experimental study (Tyr185Lys, Thr187Asp, and Arg188Ile). After mutation, Asp199 lost the salt bridge formed with Arg188 in the wild type located around loop C. Then, the loop C conformation changed and became more flexible than that of the wild type. We also detected reduced space between the toxin and the binding site in the mutant simulation, resulting in increased binding affinity to the toxin. Therefore, we propose a new Asp199 mutation that breaks the salt bridge and may produce similar selectivity to that of the Arg188 mutation.
참고문헌 (13)
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