MOLECULAR MODELING & DYNAMICS OF ION CHANNEL PROTEINS IN MEMBRANES

通过使用计算机提供的建模工具 图形实验室，我们已经能够生成一些 不同型号的甲型流感M2离子通道。我们已经插入了 这一通道进入了模型膜系统，并进行了分子 延伸到纳秒时间尺度的动力学模拟。 初步结果表明，该蛋白质保持在阿尔法状态。 螺旋束，蛋白质的闭合状态保持水分 不能通过海峡。我们计划进行进一步的结构研究 以及相关蛋白质，CGL的资源将为这些蛋白质 继续发挥重要作用。这项工作也是一个 用于研究分子的计划项目拨款的主要组成部分 导致麻醉的机制。我们这项研究的目的是 阐明M2的门控机制并论证其稳定性 显式水-磷脂双层膜中M2的结构模型 系统。我们分别进行了几次分子动力学模拟 由至少一纳秒长的轨道组成。每个人 模拟对应于不同的质子化状态 大门里有组氨酸残留物。未质子化和单质子化 发现了与质子穿梭机制有关的质子化形式 在整个弹道上保持稳定。此外， 水分子在通道内的定向有利于 有效的质子转移。相比之下，这四个人的形式 组氨酸残基是质子化的，需要在水线上 机制，在400-700的时间尺度上是不稳定和分离的 皮秒。这些结果证明了质子穿梭包括 蛋白质的组氨酸残基是最有可能的机制 M2通道中的质子输运。

Through the use of the modeling tools provided by the Computer Graphics Laboratory, we have been able to generate a number of different models of the Influenza A M2 ion channel. We have inserted this channel into model membrane systems, and have performed molecular dynamics simulations extending into the nanosecond timescale. Preliminary results indicate that the protein remains in an alpha helical bundle, and that the closed state of the protein keeps water from passing through the channel. We plan further structural studies on this, and related proteins for which the resources at the CGL will continue to play an important role. This work is also the focus of a major component of a program project grant to study the molecular mechanisms leading to anesthesia. Our aim in this study is to elucidate the gating mechanism of M2 and to demonstrate the stability of a structural model of M2 in an explicit water-phospholipid bilayer system. We have performed several molecular dynamics simulations each consisting of a trajectory at least one nanosecond long. Each simulation corresponded to a different protonation state of the histidine residues in the gate. The unprotonated and single protonated forms involved in the proton shuttle mechanism were found to be stable over the full length of the trajectory. Furthermore, the orientation of water molecules inside the channel was conducive to effective proton transfer. In contrast, the form in which all four histidine residues are protonated, required in the water-wire mechanism, was unstable and disassociated on a timescale of 400-700 picoseconds. These results demonstrate the proton shuttle involving histidine residues of the protein is the most likely mechanism of proton transport in the M2 channel.