Molecular Dynamics Simulations of Oligomeric Ion Channels within Lipid Bilayers

描述(由申请人提供)：具有嵌入离子通道的膜在许多细胞过程中起着关键作用，例如：信号、能量转换和离子电导。拟议研究的长期目标是通过使用粗粒度建模的分子建模来详细了解生物膜的生物物理性质。具体地说，对于这项提议，我们的目标是获得低聚离子通道的结构、动力学和嵌入在膜中时的组装的详细描述。即使是有限性质的结果也将通过提供合理设计针对离子通道的新型抗菌剂、抗病毒药物和药物所需的基本信息来促进公众健康。所获得的知识可能会被用来使人类能够与许多疾病作斗争，并缓解目前在治疗方面遇到的一些缺点。我们建议使用粗粒分子模拟来阐明膜离子通道显著的中尺度空间(~1&lt；m)和时间(~1ms)特征，例如假设以逐步方式发生的单体单元的形成机制。目前，无论是通过实验还是用传统的模拟方法都很难确定这些空间和时间区域。粗粒法使我们能够阐明膜的基本机制，如齐聚作用，以及膜组成对离子通道结构和功能的影响。具体目标是一系列精心计划的模拟，以检查嵌入在膜内的离子通道的相互作用：目标1是了解双层内β-螺旋肽的相互作用；目标2是了解脂双层对β-螺旋的作用和响应；目标3是了解离子通道内的螺旋-螺旋相互作用；以及目标4是计算离子通道形成的结合自由能(G)。所有AIMS的一个共同目标是量化离子通道的结构和动力学性质以及它们与膜的相互作用。如果这些目标是成功的(甚至是部分成功的)，我们应该深入了解单体多肽形成同源低聚离子通道的机制。公共卫生相关性：这项提议的目的是获得嵌入在膜内的低聚离子通道结构和动力学的详细描述。这一目标的完成将通过提供合理设计针对离子通道的新型抗菌剂、抗病毒药物和药物所需的基本信息来促进公众健康。所获得的知识有可能进一步使人类能够与许多疾病作斗争，并缓解目前在治疗方面遇到的一些缺点。

DESCRIPTION (provided by applicant): Membranes with their embedded ion channels play a crucial role in numerous cell processes such as: signaling, energy conversion, and ion conductance. The long term goal of the proposed studies is to provide a detailed understanding of the biophysical properties of biological membranes through molecular modeling using coarse grain modeling. Specifically, for this proposal, we aim to obtain a detailed description of oligomeric ion channel structure, dynamics and assembly while embedded within a membrane. Results of even a limited nature will promote public health by providing essential information needed for the rational design of novel antimicrobial, antiviral, and pharmaceutical agents which target ion channels. The knowledge gained may be use to enable mankind to combat many diseases and to alleviate some of the shortcomings currently encountered with today's therapeutics. We propose to elucidate salient mesoscale spatial (~ 1 <m) and temporal (~ 1 ms) features of membrane associated ion channels using coarse grain molecular modeling, such as the mechanism of formation from monomeric units which is hypothesized to occur in a stepwise fashion. Currently, these spatial and temporal regions are difficult to determine either experimentally or with conventional simulation methodologies. Coarse grain methods allow us to elucidate fundamental membrane mechanisms such as oligomerization, and the effect of membrane composition on structure and function of ion channels. The specific aims are a carefully planned series of simulations to examine the interactions of ion channels embedded within membranes: Aim 1 is to understand the interaction of the ?-helical peptide within the bilayer; Aim 2 is to understand the role and response of the lipid bilayer to the ? -helix; Aim 3 is to understand the helix- helix interactions within an ion channel; and Aim 4 is to calculate binding free energy (G) of formation of the ion channel. A common goal of all aims is to quantify the structural and dynamical properties of ion channels and their interactions with membranes. If these aims are successful (or even partially successful) we should gain insight into the mechanism of formation of homo-oligomeric ion channels from monomeric peptides. PUBLIC HEALTH RELEVANCE: The aim of this proposal is to obtain a detailed description of oligomeric ion channel structure and dynamics embedded within a membrane. Completion of this aim will promote public health by providing essential information needed for the rational design of novel antimicrobial, antiviral, and pharmaceutical agents which target ion channels. The knowledge gained has the potential to further enable humans to combat many diseases and to alleviate some of the shortcomings currently encountered with today's therapeutics.