Proton Paths in Models of the Hv1 Proton Channel
Proton Paths in Models of the Hv1 Proton Channel
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DOI：
10.1021/acs.jpcb.3c03960
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发表时间：
2023-09-11
影响因子：
3.3
通讯作者：
Lazaridis，Themis
中科院分区：
文献类型：
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作者：
Lazaridis，Themis
电压门控质子通道(Hv1)在许多生物过程中起着重要的作用，但对其功能缺乏详细的分子理解。开放国家和休眠国家缺乏可靠的结构是一个主要障碍。基于同源电压传感器和小鼠同源基因和磷酸酶电压传感器之间嵌合体的结构，已经建立了几个模型，但它们的有效性尚不确定。此外，对于质子转运的方式、特定残基的作用以及pH对电压门控的影响机制，也存在不同的观点。在这里，我们使用电压偏置力作用下的经典质子跳跃模拟来评估所提出的一些结构模型，并探索质子传导的机制。自相矛盾的是，针对闭合状态提出的一些模型比针对开放状态的模型更容易允许质子渗透。具有D112-R211盐桥(R3D)的开态模型比具有D112-R208盐桥(R2D)的模型更容易进行质子输运。然而，考虑到实验电导，它的渗透率似乎太高了。在所有情况下，质子都会通过电线渗透，绕过盐桥D112，而不是被D112穿梭。质子化D112的尝试由于其与精氨酸的强烈相互作用而被拒绝。与质子选择性一致，在R2D模型中没有观察到Na+渗透。作为阴性对照，Kv1.2-Kv2.1桨形嵌套电压传感器的模拟在相同条件下没有显示质子渗透，该传感器预计不会传导质子。氢键连接性图显示在D112处有收缩，但不能区分开放和关闭状态。
The voltage-gated proton channel (Hv1) plays an essential role in numerous biological processes, but a detailed molecular understanding of its function is lacking. The lack of reliable structures for the open and resting states is a major handicap. Several models have been built based on homologous voltage sensors and the structure of a chimera between the mouse homologue and a phosphatase voltage sensor, but their validity is uncertain. In addition, differing views exist regarding the mode of proton translocation, the role of specific residues, and the mechanism of pH effects on voltage gating. Here we use classical proton hopping simulations under a voltage biasing force to evaluate some of the proposed structural models and explore the mechanism of proton conduction. Paradoxically, some models proposed for the closed state allow for proton permeation more easily than models for the open state. An open state model with a D112–R211 salt bridge (R3D) allows proton transport more easily than models with a D112–R208 salt bridge (R2D). However, its permeation rate seems too high, considering experimental conductances. In all cases, the proton permeates through a water wire, bypassing the salt-bridged D112 rather than being shuttled by D112. Attempts to protonate D112 are rejected due to its strong interaction with an arginine. Consistent with proton selectivity, no Na+permeation was observed in the R2D models. As a negative control, simulations with the Kv1.2–Kv2.1 paddle-chimera voltage sensor, which is not expected to conduct protons, did not show proton permeation under the same conditions. Hydrogen bond connectivity graphs show a constriction at D112, but cannot discriminate between open and closed states.