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 甲型流感M2离子通道的不同模型。 我们已经插入了 这种通道进入模型膜系统， 扩展到纳秒时间尺度的动力学模拟。 初步结果表明，这种蛋白质仍然是α- 螺旋束，并且蛋白质的封闭状态保持水 穿过海峡。 我们计划进一步的结构研究 以及相关蛋白质，CGL的资源将 继续发挥重要作用。 这项工作也是一个重点 研究分子生物学的计划项目赠款的主要组成部分 导致麻醉的机制。 我们这项研究的目的是 阐明M2的门控机制并证明稳定性 M2在明确的水-磷脂双层中的结构模型 系统 我们进行了几次分子动力学模拟， 由至少一纳秒长的轨迹组成。 每个 模拟对应于不同的质子化状态的 门中的组氨酸残基。 未质子化的单一 质子化的形式参与质子穿梭机制被发现 在整个轨道上保持稳定 而且 水分子在通道内的取向有助于 有效的质子转移。 与此相反，这四种形式 组氨酸残基被质子化，这是水线中所需的 在400-700年的时间尺度上， 皮秒 这些结果表明，质子穿梭涉及 组氨酸残基的蛋白质是最有可能的机制， M2通道中的质子传输。

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.