Molecular dynamics simulations of oligomeric ion channels within lipid bilayers

描述（由申请人提供）：膜及其嵌入的离子通道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分子建模提供对这些生物膜的生物物理特性的详细了解。在这个提议中，我们的目标是获得嵌入膜内的低聚离子通道结构和动力学的详细描述。这一目标的完成将为合理设计针对离子通道的新型抗菌、抗病毒和药物制剂提供必要的信息，从而促进公共卫生。所获得的知识有可能进一步使人类能够战胜许多疾病，并减轻当今治疗方法目前遇到的一些缺点。我们建议使用粗颗粒分子模型来阐明膜相关离子通道的空间（约1微米）和时间（约1毫秒）中尺度显著特征，例如单体肽的形成机制。目前，这些空间和时间区域很难通过实验或传统的模拟方法确定。这些新颖的粗粒方法使我们能够阐明基本的膜机制，如寡聚化。具体的目标是仔细计划的一系列模拟，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。计算将从单跨膜两性肽的结构和动力学特性开始，同时我们将分析由肽对脂质膜造成的扰动。此外，我们将测量由几种跨膜两性肽组成的同质寡聚离子通道的结构和动力学特性。最终，我们的目标是计算离子通道形成的结合自由能，并阐明单体肽形成同质寡聚离子通道的机制。

DESCRIPTION (provided by applicant): Membranes and 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 these biological membranes through molecular modeling. For this proposal, we aim 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. We propose to elucidate the spatial (about 1 micrometer) and temporal (about 1 millisecond) mesoscale salient features of membrane associated ion channels using coarse grain molecular modeling, such as the mechanism of formation from monomeric peptides. Currently, these spatial and temporal regions are difficult to determine either experimentally or with conventional simulation methodologies. These novel coarse grain methods allow us to elucidate fundamental membrane mechanisms such as oligomerization. The specific aims are a carefully planned series of simulations to examine the interactions of ion channels embedded within membranes. The goal is to quantify the structural and dynamical properties of ion channels and their interactions with membranes. Calculations will begin with the structural and dynamical characterization of single transmembrane amphipathic peptides, and we will simultaneously analyze the perturbations caused by the peptide on the lipid membrane. Additionally, we will measure the structural and dynamical characteristics of homo-oligomeric ion channels composed of several transmembrane amphipathic peptides. Ultimately, we aim to calculate the binding free energy of ion channel formation, and elucidate the mechanism of formation of homo-oligomeric ion channels from monomeric peptides.