Building Computational Models to Probe Membrane Fusion

Michael L.天普大学的Klein得到了化学理论，模型和计算方法项目的支持，该项目将新的计算算法和方法与领导级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囊泡将神经递质递送至质膜时，融合蛋白增强囊泡-膜融合的固有缓慢速率。长期的目标是阐明融合蛋白发挥的机制作用。融合过程的大小，时间尺度和复杂性要求使用粗粒模拟方法，如PI小组开发的脂质囊泡自组装和表面活性剂和大分子表现出的相关现象。突触囊泡的大小是现在用最先进的硬件进行分子动力学模拟所能达到的。当前的挑战是处理融合蛋白，然后在大规模并行LAMMPS模拟代码中构建一个完整的模拟包，最终使用校准到组件真实模拟的模型探索完整的融合过程。该提案涉及国际合作，以进一步阐述带电脂质及其与蛋白质和反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，成功将影响基础科学和应用科学，从化学和生物学到纳米技术。拟议的研究将在计算分子科学研究所（ICMS）进行，利用最先进的计算机模拟来模拟关键的生物过程。自2009年成立以来，ICMS已经产生了新的初级教师招聘与计算的兴趣。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，这些课程影响了教育-化学，生物学，物理学，计算机科学和数学的教师，博士后，格拉德生和本科生利用ICMS的专业知识。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已经接受了对公众和整个社会的重大推广（费城科学博览会和富兰克林研究所）。展望未来，它将整合其人力资源开发工作与现有的计划，如TU-teach，这有利于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，物理学，材料科学，药理学和神经科学。ICMS的毕业生已被行业雇用，并进入终身职位的职位，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.