Molecular Dynamics Simulations of Oligomeric Ion Channels within Lipid Bilayers

描述（由申请人提供）：具有嵌入式离子通道的膜在许多细胞过程中起着至关重要的作用，例如：信号传导、能量转换和离子电导。提出的研究的长期目标是通过使用粗粒建模的分子建模提供对生物膜的生物物理性质的详细理解。具体来说，对于这个建议，我们的目标是获得一个详细的描述，低聚离子通道的结构，动力学和组装，而嵌入在膜内。即使是有限的性质的结果将通过提供合理设计靶向离子通道的新型抗微生物剂、抗病毒剂和药剂所需的基本信息来促进公共健康。所获得的知识可以用于使人类能够与许多疾病作斗争，并减轻当今治疗方法所遇到的一些缺点。我们建议使用粗粒分子模型来阐明膜相关离子通道的中尺度空间（~ 1 <m）和时间（~ 1 ms）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，这些空间和时间区域是很难确定的实验或与传统的模拟方法。粗粒方法使我们能够阐明基本的膜机制，如寡聚化，和膜组成对离子通道的结构和功能的影响。具体的目标是一个精心策划的一系列模拟，以检查嵌入膜内的离子通道的相互作用：目的1是了解？双分子层内的螺旋肽;目的2是了解的作用和响应的脂质双分子层？- 螺旋;目的3是了解离子通道内的螺旋-螺旋相互作用;目的4是计算离子通道形成的结合自由能（G）。所有目标的一个共同目标是量化离子通道的结构和动力学性质及其与膜的相互作用。如果这些目标是成功的（甚至部分成功），我们应该深入了解从单体肽形成同源寡聚离子通道的机制。公共卫生相关性：本提案的目的是获得一个详细的描述寡聚离子通道的结构和动力学嵌入在膜内。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、抗病毒剂和药剂所需的基本信息来促进公共健康。所获得的知识有可能进一步使人类能够对抗许多疾病，并减轻当今治疗方法所遇到的一些缺点。

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.