LARGE SCALE MD SIMULATIONS OF ANESTHETIC EFFECTS ON ION CHANNELS

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 我们研究的最终目的是了解全身麻醉的分子机制。我们的计算工作的直接目标是引出蛋白质运动的分子细节，这些分子细节很难用实验方法直接观察到，但对理解通道蛋白的麻醉作用可能至关重要。我们将重点关注GLIC，其通道功能可被全身麻醉药抑制。该研究的具体目的包括：（1）在不存在麻醉剂的情况下（对照系统），在完全水合的膜贴片中进行100 ns或甚至更长的MD模拟;（2）在存在两种临床使用的麻醉剂（丙泊酚和依托咪酯）的情况下进行并行MD模拟;（3）基于目的1和2中生成的结构计算Na+穿过通道的PMF。研究假设：麻醉剂与EC-TM界面处的驱动点和通道内的残留物的相互作用将引起GLIC的结构和动力学的显著变化。在扩展的MD模拟后，麻醉作用将被编码为三级和四级结构水平的全局变化。在有无麻醉剂的情况下，对这些模拟结构的PMF计算将为麻醉剂如何介导GLIC通道的功能提供有价值的见解。从拟议的研究中获得的知识将是可转移的，以了解麻醉剂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.