Molecular dynamics simulations of oligomeric ion channels within lipid bilayers

描述(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分子模拟提供对这些生物膜的生物物理性质的详细了解。对于这一提议，我们的目标是获得嵌入在膜中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。我们建议使用粗粒分子模型来解释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，例如单体多肽的形成机制。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。这些新的粗粒方法使我们能够阐明齐聚等基本的膜机理。具体目标是一系列精心策划的模拟，以检查嵌入膜内的离子通道的相互作用。其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。计算将从单个跨膜两亲性多肽的结构和动力学特征开始，同时我们将分析多肽对脂膜的扰动。此外，我们还将测量由几个跨膜两亲性多肽组成的同源低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，并阐明单体多肽形成均低聚离子通道的机制。

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.