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.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 在此续订应用中，我们要求使用仿真方法继续研究对几个膜转运蛋白和通道的机制进行调查。将研究几种活跃的转运蛋白，这些转运蛋白将在活细胞中使用各种能源来进行功能。此外，我们还将继续研究对另一种膜相关现象的研究，即膜结合的机制和血液凝结因子的激活，这构成了过去的融资期间最有生产力的项目，以及UIUC的5个实验室之间的强大协作工作。实际上，所有项目都是与领先的实验组密切合作进行的。所有项目都解决了相当缓慢的过程，因此需要长时间的模拟。此外，由于需要明确表示脂质和水，这些脂质和水在转运蛋白的机理中起着作用，并且由于结构的复杂性，需要模拟大分子组件。这样的计算只能使用高级TeraGRID计算资源进行。这些蛋白质功能的大小和复杂性对计算研究构成了巨大的挑战。然而，在最后一个资金期间，我们通过进度报告中的几篇发表论文证明了大规模的MD模拟确实可以显着提高我们对这些生物分子中能量偶联和转运现象的分子机制的理解。由于空间有限，需要描述6个项目，因此我们将我们初步结果的进度和讨论完全授予了进度报告。我们在过去的资金期间广泛使用分配是这种生物分子系统计算需求的最有力的证据。但是，我们注意到，我们在过去的资金周期中使用了分配的时间极有效，并创建了创纪录的出版物（16;请参阅进度报告）。我们想对拟议的模拟的长度进行一般性的澄清，这可能被认为是“不合理的”方面。所有项目都解决了相当缓慢的生物分子过程（至少在微秒的顺序上）。因此，从技术的角度来看，即使比本应用程序中描述的阶数也比本应用程序中描述的阶更长。但是，我们意识到，目前无法全面描述此类过程（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，为了提供有望令人满意的理由，几乎在所有情况下，我们都将基于相同或可比的系统/现象的现有基准（大多数出版）的拟议仿真长度。