Building Computational Models to Probe Membrane Fusion

建立计算模型来探测膜融合

• 批准号: 1212416
• 负责人: Michael Klein
• 金额: $ 40.6万
• 依托单位: Temple University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1212416&HistoricalAwards=false
• 关键词: Building; Computational; Models; Probe; Membrane

Michael L. Klein at Temple University is supported by the Chemical Theory, Models and Computational Methods program in research coupling novel computational algorithms and methods with leadership-class HPC resources to understand membrane fusion, a key process in viral infection and neurotransmitter release at the synapse. In the latter, fusion proteins enhance the intrinsic slow rate of vesicle-membrane fusion when a 30-50 nm vesicle delivers neurotransmitter to the plasma membrane. The long-term aim is to elucidate the mechanistic role played fusion proteins. The size, time-scale, and complexity of the fusion process demands the use of coarse grain simulation methodologies such as those developed by the PI's group for lipid-vesicle self-assembly and related phenomena exhibited by surfactants and macromolecules. Synaptic vesicles are of the size just now accessible with molecular dynamics simulation on state-of-the-art hardware. The immediate challenge is to handle the fusion proteins and then build a complete simulation package - within the massively parallel LAMMPS simulation code - to eventually explore the complete fusion process using models calibrated to realistic simulations of the components. The proposal involves an international collaboration to further elaborate the needed models for charged lipids and their interaction with proteins and counter ions. The closely related process of vesicle-vesicle fusion is broadly relevant to research in surfactant science and nanotechnology. Thus, success will impact fundamental and applied science ranging from chemistry and biology to nanotechnology. The proposed research on using state of the art computer simulation to model key biological processes will be carried out in the Institute for Computational Molecular Science (ICMS). Since its creation in 2009, ICMS has spawned new junior faculty hires with an interest in computation. ICMS already offers informal classes on parallel programming and HPC tools, and classes on molecular modeling, which have impacted education -- faculty, post-docs, grad students and undergraduates in Chemistry, Biology, Physics, Computer Science, and Mathematics take advantage of the expertise residing in ICMS. The long-term goal is to develop these informal offerings into formal undergraduate courses and masters degree programs. ICMS has already embraced significant outreach to the public and society at large (Philadelphia Science Fair and the Franklin Institute). Going forward, it will integrate its HR development efforts with existing programs such as TU-teach, which benefit undergraduates and local high school science teachers. ICMS will continue to host extended visits of scientists from around the World plus graduate students from other labs who can enjoy the intellectual diversity of ICMS research -- chemistry, physics, materials science, pharmacology, and neuroscience. ICMS graduates have been hired by industry and into tenure track positions in academe, which attests to the important of its societal impact.

坦普尔大学的迈克尔·克莱因（Michael L.在后者中，当30-50 nm囊泡将神经递质转移到质膜时，融合蛋白会增强囊泡 - 膜融合的固有缓慢速率。长期的目的是阐明机械作用的融合蛋白。融合过程的大小，时间尺度和复杂性需要使用粗粒仿真方法，例如PI组开发的脂质 - 维化合物自组装和相关现象，表面活性剂和大分子表现出相关现象。突触囊泡的大小刚好在最新硬件上的分子动力学模拟时可以访问。直接的挑战是处理融合蛋白，然后在大规模并行的LAMMPS模拟代码中构建一个完整的仿真软件包，以最终使用校准的组件的现实仿真模型来探索完整的融合过程。该提案涉及一项国际合作，以进一步阐述带电脂质的所需模型及其与蛋白质和反离子的互动。囊泡叶片融合的紧密相关的过程与表面活性剂科学和纳米技术的研究广泛有关。因此，成功将影响从化学和生物学到纳米技术的基本科学和应用科学。提出的关于使用最先进的计算机模拟对关键生物学过程进行建模的研究将在计算分子科学研究所（ICMS）进行。自2009年创建以来，ICMS催生了新的初级教师雇用，对计算感兴趣。 ICMS已经提供了有关并行编程和HPC工具的非正式课程，以及有关分子建模的课程，这些课程影响了教育 - 教师，培训后，研究生，研究生和本科生在化学，生物学，物理，计算机，计算机科学和数学方面都利用ICMS中的专业知识。长期目标是将这些非正式产品开发为正式的本科课程和硕士学位课程。 ICMS已经在整个公众和社会（费城科学博览会和富兰克林学院）接受了大量的宣传。展望未来，它将将其人力资源开发工作与TU-TEACH等现有计划相结合，这些计划受益于本科生和当地的高中科学教师。 ICMS将继续举办来自世界各地的科学家的扩展访问，以及其他实验室的研究生，他们可以享受ICMS研究的智力多样性 - 化学，物理，材料科学，药理学和神经科学。 ICMS毕业生已由行业雇用，并在Academe中担任终身轨道职位，这证明了其社会影响力的重要意义。