Dong Chuqiao, Kern Nathan R, Anderson Kristin R, Zhang X Frank, Miwa Julie M, Im Wonpil
Department of Mechanical Engineering and Mechanics, Lehigh University, Bethlehem, Pennsylvania 18015, United States.
Department of Computer Science and Engineering, Lehigh University, Bethlehem, Pennsylvania 18015, United States.
J Phys Chem B. 2020 May 21;124(20):4017-4025. doi: 10.1021/acs.jpcb.0c00159. Epub 2020 Apr 9.
Nicotinic acetylcholine receptors (nAChRs) participate in diverse biological processes, such as mood, learning, and addiction. Glycosylphosphatidylinositol-linked lynx1 is an allosteric modulator of nAChR function, including shifts in agonist sensitivity, reduced desensitization, and slower recovery from desensitization. This modulation is thought to be achieved by lynx1's interaction with nAChR subunits, particularly at the α4:α4 interface. In this study, we used molecular modeling and simulation to study the structure, dynamics, and interactions of lynx1 when bound to nAChRs, as well as unbound, monomeric lynx1 in membranes. Though lynx1 structures are similar in both states, its dynamics is more restricted in the bound state than in the unbound one. When bound, interactions between lynx1 and nAChR are observed to be maintained throughout the simulations. Of particular note, lynx1 demonstrates prolonged interactions with the receptor C-loop in one of the nAChR α4 subunits, a region important for agonist binding and possibly the transition between open/closed states. During interactions with lynx1, an α4 C-loop tends to be restricted in either a closed or open state, whereas the C-loop state transitions are more evident when lynx1 is unbound. Interestingly, the conformational change of the C-loop is stochastic, suggesting that lynx1 can influence nAChR (critical for its multimodal action), for instance, by shifting its agonist sensitivity and recovery from desensitization.
烟碱型乙酰胆碱受体（nAChRs）参与多种生物学过程，如情绪、学习和成瘾。糖基磷脂酰肌醇连接的lynx1是nAChR功能的变构调节剂，包括激动剂敏感性的改变、脱敏作用的降低以及脱敏后恢复速度的减慢。这种调节作用被认为是通过lynx1与nAChR亚基的相互作用实现的，尤其是在α4:α4界面处。在本研究中，我们使用分子建模和模拟来研究lynx1与nAChRs结合时以及在膜中未结合的单体lynx1的结构、动力学和相互作用。尽管lynx1在两种状态下的结构相似，但其动力学在结合状态下比未结合状态下受到更多限制。结合时，在整个模拟过程中观察到lynx1与nAChR之间的相互作用得以维持。特别值得注意的是，lynx1在nAChR的一个α4亚基中与受体C环表现出长时间的相互作用，该区域对激动剂结合以及可能对开放/关闭状态之间的转变很重要。在与lynx1相互作用期间，α4 C环倾向于限制在关闭或开放状态，而当lynx1未结合时，C环状态的转变更为明显。有趣的是，C环的构象变化是随机的，这表明lynx1可以影响nAChR（对其多模式作用至关重要），例如，通过改变其激动剂敏感性和脱敏后的恢复情况。
