Department of Biochemistry, University of Oxford, Oxford, United Kingdom.
Biophys J. 2010 Apr 21;98(8):1558-65. doi: 10.1016/j.bpj.2009.12.4321.
Gating-modifier toxins inhibit voltage-gated ion channels by binding the voltage sensors (VS) and altering the energetics of voltage-dependent gating. These toxins are thought to gain access to the VS via the membrane (i.e., by partitioning from water into the membrane before binding the VS). We used serial multiscale molecular-dynamics (MD) simulations, via a combination of coarse-grained (CG) and atomistic (AT) simulations, to study how the toxin VSTx1, which inhibits the archeabacterial voltage-gated potassium channel KvAP, interacts with an isolated membrane-embedded VS domain. In the CG simulations, VSTx1, which was initially located in water, partitioned into the headgroup/water interface of the lipid bilayer before binding the VS. The CG configurations were used to generate AT representations of the system, which were subjected to AT-MD to further evaluate the stability of the complex and refine the predicted VS/toxin interface. VSTx1 interacted with a binding site on the VS formed by the C-terminus of S1, the S1-S2 linker, and the N-terminus of S4. The predicted VS/toxin interactions are suggestive of toxin-mediated perturbations of the interaction between the VS and the pore domain of Kv channels, and of the membrane. Our simulations support a membrane-access mechanism of inhibition of Kv channels by VS toxins. Overall, the results show that serial multiscale MD simulations may be used to model a two-stage process of protein-bilayer and protein-protein interactions within a membrane.
门控修饰毒素通过结合电压传感器（VS）并改变电压门控的能量学来抑制电压门控离子通道。这些毒素被认为通过膜进入 VS（即在与 VS 结合之前通过从水中分配到膜中）。我们使用串联多尺度分子动力学（MD）模拟，通过粗粒化（CG）和原子模拟（AT）的组合，研究了抑制古细菌电压门控钾通道 KvAP 的毒素 VSTx1 如何与分离的膜嵌入式 VS 结构域相互作用。在 CG 模拟中，最初位于水中的 VSTx1 在与 VS 结合之前分配到头基团/水界面的脂质双层中。CG 配置用于生成系统的 AT 表示，对其进行 AT-MD 以进一步评估复合物的稳定性并细化预测的 VS/毒素界面。VSTx1 与由 S1 的 C 末端、S1-S2 接头和 S4 的 N 末端形成的 VS 上的结合位点相互作用。预测的 VS/毒素相互作用表明毒素介导了 VS 和 Kv 通道的孔域之间相互作用以及膜的扰动。我们的模拟支持 VS 毒素抑制 Kv 通道的膜进入机制。总体而言，结果表明串联多尺度 MD 模拟可用于模拟膜内蛋白质-双层和蛋白质-蛋白质相互作用的两阶段过程。
