Building Computational Models to Probe Membrane Fusion

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，他的研究将新的计算算法和方法与领导级HPC资源结合起来，以理解膜融合，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的囊泡将神经递质传递到质膜时，融合蛋白增强了囊泡-膜融合的固有缓慢速率。长期目标是阐明融合蛋白所起的机制作用。融合过程的大小、时间尺度和复杂性要求使用粗颗粒模拟方法，例如PI小组开发的脂质囊泡自组装和表面活性剂和大分子所表现出的相关现象。突触囊泡的大小现在可以用最先进的硬件进行分子动力学模拟。当前的挑战是处理融合蛋白，然后建立一个完整的模拟包-在大规模并行LAMMPS模拟代码-最终探索完整的融合过程使用模型校准到组件的现实模拟。该提案涉及国际合作，以进一步阐述所需的带电脂质及其与蛋白质和反离子相互作用的模型。与之密切相关的囊泡-囊泡融合过程与表面活性剂科学和纳米技术的研究有着广泛的关系。因此，成功将影响从化学和生物学到纳米技术的基础科学和应用科学。关于使用最先进的计算机模拟来模拟关键生物过程的拟议研究将在计算分子科学研究所（ICMS）进行。自2009年成立以来，ICMS已经招聘了一批对计算感兴趣的新初级教员。ICMS已经提供了关于并行编程和高性能计算工具的非正式课程，以及关于分子建模的课程，这些课程对教育产生了影响——化学、生物、物理、计算机科学和数学领域的教师、博士后、研究生和本科生可以利用ICMS的专业知识。长期目标是将这些非正式课程发展成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（费城科学博览会和富兰克林研究所）进行了重大的拓展。展望未来，它将把人力资源开发工作与TU-teach等现有项目整合起来，这些项目将惠及本科生和当地高中科学教师。ICMS将继续接待来自世界各地的科学家和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的毕业生已被工业界聘用，并在学术界获得终身职位，这证明了其社会影响的重要性。

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.