LARGE SCALE MD SIMULATIONS OF ANESTHETIC EFFECTS ON ION CHANNELS

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 本研究的最终目的是了解全身麻醉的分子机制。我们计算工作的直接目标是得出蛋白质运动的分子细节，这些细节很难用实验方法直接观察到，但对了解麻醉对通道蛋白质的作用可能至关重要。我们将重点关注GLIC，它的通道功能可以被全麻药抑制。这项研究的具体目标包括(1)在没有麻醉药(控制系统)的情况下，在完全水合的膜片上进行100 ns甚至更长时间的MD模拟；(2)在两种临床使用的麻醉药(异丙酚和依托咪酯)存在的情况下进行并行MD模拟；(3)根据Aim 1和2中产生的结构计算跨通道的Na+的PMF。在扩展的MD模拟之后，麻醉效应将被编码为三级和四级结构水平上的全局变化。在没有麻醉药和有麻醉剂存在的情况下，对这些模拟结构的PMF计算将为麻醉剂如何调节GLIC通道的功能提供有价值的见解。从这项拟议的研究中获得的知识将可用于理解麻醉对中枢神经系统中其他同源通道蛋白的作用。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The ultimate goal of our study is to understand the molecular mechanisms of general anesthesia. The immediate objective of our computational efforts is to elicit the molecular details of protein motions that are difficult to observe directly with experimental methods but potentially crucial to the understanding of anesthetic actions on the channel proteins. We will focus on GLIC whose channel function can be inhibited by general anesthetics. The specific aims for the study include (1) to perform a 100-ns or even longer MD simulation in a fully hydrated membrane patch in the absence of anesthetics (a control system); (2) to conduct parallel MD simulations in the presence of two clinically used anesthetics (propofol and etomidate); (3) to calculate PMFs of Na+ across the channel based on the structures generated in Aim 1 and 2. Hypotheses for the study: anesthetic interaction with the actuation points at the EC-TM interface and residues inside the channel will introduce significant changes in the structure and dynamics of GLIC. The anesthetic effects will be encoded as global changes at tertiary and quaternary structural level after extended MD simulations. The PMF calculations on these simulated structures in the absence and presence of anesthetics will offer valuable insights into how anesthetics mediate the function of GLIC channel. The knowledge acquired from the proposed study will be transferable for understanding anesthetic actions on other homologous channel proteins in the central nervous system.