LARGE SCALE SIMULATION OF MEMBRANE CHANNELS AND TRANSPORTERS

膜通道和转运体的大规模模拟

• 批准号: 7956352
• 负责人: Emad Tajkhorshid
• 金额: $ 0.08万
• 依托单位: CARNEGIE-MELLON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7956352
• 关键词: Address; Benchmarking; Binding; Biomedical Research; Blood Coagulation Factor; Cells; Collaborations; Computer Retrieval of Information on Scientific Projects Database; Coupling; Energy-Generating Resources; Funding; Grant; High Performance Computing; Institution; Investigation; Ion Channel; Length; Life; Lipids; Membrane; Membrane Transport Proteins; Methodology; Molecular; Paper; Play; Process; Progress Reports; Publications; Publishing; Reporting; Request for Applications; Research; Research Personnel; Resources; Role; Simulate; Source; Structure; System; Time; United States National Institutes of Health; Water; base; computer studies; computing resources; large scale simulation; molecular assembly/self assembly; protein function; simulation

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. In this renewal application, we request time to continue our investigation of the mechanism of several membrane transporters and channels using simulation methodologies. Several active transporters that use various source of energy in a living cell for their function will be investigated. Furthermore, we will also continue our research on another membrane associated phenomenon, namely mechanism of membrane binding and activation of blood coagulation factors, which constitutes the most productive project over the past funding period, and a strong collaborative effort between 5 labs at UIUC. In fact, all of the projects are conducted in close collaboration with leading experimental groups. All Projects address rather slow processes, thus, requiring long simulations. Furthermore, due to the need of explicit representation of the lipid and water, which play role in the mechanism of transporters, and due to the complexity of the structure, large molecular assemblies need to be simulated. Such calculations can only be carried out with the advanced TeraGrid computational resources. The size and complexity of the function of these proteins pose a great challenge for computational studies. Over the last funding period, however, we have demonstrated through several published papers reported in the Progress Report, that large scale MD simulations can indeed significantly advance our understanding of the molecular mechanisms of energy coupling and transport phenomena in these biomolecules. Due to limited space and the need to describe 6 projects, we have delegated the progress and discussion of our preliminary results completely to the Progress Report. Our extensive use of the allocation over the past funding period is the strongest evidence for the computational demands of such biomolecular systems. We note, however, that we have used the allocated time extremely productively and produced a record number of publications (16; please see Progress Report) over the past funding cycle. We would like to give a general clarification with regard to the length of the proposed simulations, which might be perceived as an "unjustified" aspect. All of the projects address rather slow biomolecular processes (at least on the order of microsecond). As such, even orders of magnitude longer simulations than those described in this application can be easily justified from a technical point of view. However, we realize that such processes (e.g., complete transport cycle) cannot be currently described in their entirety, and we can only expect to cover some of the steps involved in such processes. Therefore, in order to provide a justification that will hopefully be satisfactory, almost in all cases we will base the length of the proposed simulations on our existing benchmarks (mostly published) of the same or comparable systems/phenomena.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 中心，不一定是研究者的机构。 在此更新应用中，我们请求时间使用模拟方法继续研究几种膜转运蛋白和通道的机制。将研究几种在活细胞中使用各种能源来发挥其功能的主动转运蛋白。此外，我们还将继续研究另一种膜相关现象，即膜结合和凝血因子激活的机制，这是过去资助期间最富有成效的项目，也是伊利诺伊大学香槟分校（UIUC）5个实验室之间强有力的合作努力。事实上，所有项目都是与领先的实验小组密切合作进行的。所有项目都涉及相当缓慢的过程，因此需要长时间的模拟。此外，由于需要明确表示在转运蛋白机制中发挥作用的脂质和水，并且由于结构的复杂性，需要模拟大分子组装体。此类计算只能使用先进的 TeraGrid 计算资源来进行。这些蛋白质的大小和功能的复杂性对计算研究提出了巨大的挑战。然而，在上一个资助期间，我们通过进展报告中报告的几篇已发表的论文证明，大规模MD模拟确实可以显着促进我们对这些生物分子中能量耦合和传输现象的分子机制的理解。由于篇幅有限，需要描述6个项目，我们将初步结果的进展和讨论完全委托给进度报告。我们在过去的资助期间对分配的广泛使用是此类生物分子系统的计算需求的最有力证据。然而，我们注意到，在过去的资助周期中，我们非常高效地利用了分配的时间，并出版了创纪录数量的出版物（16 份；请参阅进度报告）。我们想对拟议模拟的长度进行一般性澄清，这可能被视为“不合理”的方面。所有项目都涉及相当慢的生物分子过程（至少在微秒级）。因此，从技术角度来看，甚至比本申请中描述的模拟长几个数量级的模拟也可以很容易地被证明是合理的。然而，我们意识到目前无法完整描述此类过程（例如完整的运输周期），我们只能期望涵盖此类过程中涉及的一些步骤。因此，为了提供一个令人满意的理由，几乎在所有情况下，我们都会根据相同或可比系统/现象的现有基准（大部分已发布）来确定拟议模拟的长度。