Molecular Modeling of Ion Channel and Other Membrane Proteins

分子建模核心与Robert Guys博士长期合作 在细胞生物学实验室。我们采取了进化的方法来研究离子 通道蛋白，检查伴随Na+和 Ca ~（2+）通道与K ~+通道的区别。在这 追求，我们最近发表了原核NaChBac通道的模型，这是一个 祖先K+通道与后代Na+和Ca 2+通道之间的进化联系。 这些模型解释了孔隙中氨基酸残基类型的微妙平衡， 特定的离子选择性，以及电压传感器和激活门的耦合。我们 现在正在使用这些结果作为垫脚石，以模拟更复杂的真核Na+， Ca 2+通道通过与实验小组的合作，我们将使用这些模型来 分析Ca 2+通道阻滞剂的分子药理学（在治疗 高血压和心脏病，并可能作为抗真菌剂），并更好地 了解与遗传疾病相关的突变如何改变Ca 2+的门控特性 渠道最近，我们也重新审视了我们过去的工作建模的离子通道结构 由与阿尔茨海默病相关的淀粉样β肽（ABP）形成。虽然它曾经 尽管人们认为老年痴呆症是由大的纤维结构引起的，但最近的许多研究表明， 表明长时程增强的抑制导致了短期记忆的丧失 和负责细胞死亡的神经毒性是由于较小的低聚物组装， 肽。最近的研究也表明并证实，神经毒性涉及 低聚物与膜的相互作用，ABP确实形成跨膜离子 渠道然而，不幸的是，直接的实验测定受到了 ABP的水性和膜结合寡聚结构对以下事实非常敏感： 环境的具体情况，并随着时间的推移而变化。因此，我们更新了我们的 通过结合所有最近的实验数据和计算结果， 分子模拟技术我们准备发表两篇论文， 长纤维和离子通道结构的发展，从最小的协会， 水溶性和膜结合ABP。我们现在将探讨这些模型如何帮助设计 修饰肽以形成更稳定的结构测定组装，以及它们如何 作为药物设计的目标。我们也一直在模拟朊病毒蛋白的结构 (PrP)，具有与ABP相似的氨基酸序列片段。这些模型旨在 有助于药物开发，以对抗由PrP引起的海绵状脑病。

The Molecular Modeling Core enjoys a long-standing collaboration with Dr. Robert Guys section in the Lab of Cell Biology. We have taken an evolutionary approach to the study of ion channel proteins, examining the structural changes that accompanied the development of Na+ and Ca2+ channels from K+ channels by making representative models of each subfamily. In this pursuit, we have recently published models of the prokaryotic NaChBac channel, which is an evolutionary link between the ancestor K+ channels and the descendent Na+ and Ca2+ channels. The models explain the delicate balance of amino acid residue types in the pore that determine the specific ion selectivity, and the coupling of the voltage-sensor and activation gate. We are now using these results as a stepping stone to model the more complex eukaryotic Na+ and Ca2+ channels. In collaboration with experimental groups, we will be using these models to analyze the molecular pharmacology of Ca2+ channel blockers (important in treating hypertension and heart disease in humans and potentially as antifungicides) and to better understand how mutations associated with genetic diseases alter the gating properties of Ca2+ channels. Recently, we have also revisited our past work modeling the ion channel structures formed by the Amyloid-Beta Peptide (ABP) associated with Alzheimers disease. While it used to be thought that Alzheimers was caused by large fibril structures, numerous recent studies now indicate that the inhibition of long-term potentiation responsible for short-term memory loss and the neurotoxicity responsible for cell death are due to smaller oligomeric assemblies of the peptides. Recent studies also indicate and confirm that the neurotoxity involves interactions of the oligomers with membranes and that ABP indeed forms transmembrane ion channels. Unfortunately, however, direct experimental determination has been hampered by the fact that both aqueous and membrane-bound oligomeric structures of ABP are very sensitive to the specifics of the environment, and change over time. Consequently, we have updated our modeling of ABP structures by combining all the recent experimental data with computational molecular modeling techniques. We are about ready to publish two papers that trace the development of both long fibrils and ion channel structures from the smallest associations of aqueous-soluble and membrane-bound ABP. We will now explore how these models can help design modified peptides to form more stable assemblies for structure determination, and how they can serve as targets for drug design. We have also been modeling structures of the Prion Protein (PrP), which has segments of amino acid sequence similar to ABP. These models are intended to help pharmaceutical development to combat the spongiform encephalopathies caused by PrP.