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.

天普大学的 Michael L. Klein 得到了化学理论、模型和计算方法项目的支持，该项目将新颖的计算算法和方法与领先级 HPC 资源相结合，以了解膜融合，这是病毒感染和突触神经递质释放的关键过程。在后者中，当 30-50 nm 囊泡将神经递质传递到质膜时，融合蛋白增强了囊泡-膜融合的固有慢速。长期目标是阐明融合蛋白所发挥的机制作用。融合过程的规模、时间尺度和复杂性要求使用粗粒模拟方法，例如 PI 小组开发的用于脂质囊泡自组装以及表面活性剂和大分子表现出的相关现象的方法。突触小泡的大小目前可以通过在最先进的硬件上进行分子动力学模拟来实现。眼前的挑战是处理融合蛋白，然后在大规模并行 LAMMPS 模拟代码中构建完整的模拟包，最终使用针对组件的真实模拟进行校准的模型来探索完整的融合过程。该提案涉及国际合作，以进一步详细阐述带电脂质及其与蛋白质和抗衡离子相互作用所需的模型。囊泡-囊泡融合的密切相关过程与表面活性剂科学和纳米技术的研究广泛相关。因此，成功将影响从化学、生物学到纳米技术的基础和应用科学。拟议的使用最先进的计算机模拟来模拟关键生物过程的研究将在计算分子科学研究所（ICMS）进行。自 2009 年成立以来，ICMS 已聘请了一批对计算感兴趣的新初级教师。 ICMS 已经提供了关于并行编程和 HPC 工具的非正式课程以及分子建模课程，这些课程对教育产生了影响——化学、生物学、物理、计算机科学和数学领域的教师、博士后、研究生和本科生利用ICMS 拥有专业知识。长期目标是将这些非正式课程发展为正式的本科课程和硕士学位课程。 ICMS 已经对公众和整个社会进行了重大推广（费城科学博览会和富兰克林研究所）。展望未来，它将把人力资源开发工作与 TU-teach 等现有项目相结合，使本科生和当地高中科学教师受益。 ICMS 将继续接待来自世界各地的科学家以及来自其他实验室的研究生的长期访问，他们可以享受 ICMS 研究的知识多样性——化学、物理、材料科学、药理学和神经科学。 ICMS 毕业生已被业界聘用并进入学术界获得终身教职，这证明了其社会影响的重要性。