Building Computational Models to Probe Membrane Fusion

天普大学的Michael L.Klein在化学理论、模型和计算方法计划的支持下进行了一项研究，将新的计算算法和方法与领先的HPC资源相结合，以了解膜融合，膜融合是病毒感染和突触释放神经递质的关键过程。在后者中，当30-50 nm的囊泡将神经递质递送到质膜时，融合蛋白提高了囊泡-膜融合的固有慢速。其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粒模拟方法，例如PI的小组开发的用于脂泡自组装和表面活性剂和大分子表现出的相关现象的方法。突触囊泡的大小刚刚可以通过分子动力学模拟在最先进的硬件上实现。迫在眉睫的挑战是处理融合蛋白质，然后在大规模并行的LAMMPS模拟代码中建立一个完整的模拟包，以使用经过校准的模型来最终探索完整的融合过程，以真实地模拟组件。该提案涉及一项国际合作，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-囊泡融合过程与表面活性剂科学和纳米技术的研究具有广泛的相关性。因此，成功将影响从化学、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催生了一批对计算感兴趣的初级教员。ICMS已经开设了关于并行编程和HPC工具的非正式课程，以及关于分子建模的课程，这些课程已经对教育产生了影响--化学、生物、物理、计算机科学和数学的教职员工、博士后、研究生和本科生都利用了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已经接受了对公众和整个社会(费城科学博览会和富兰克林研究所)的重大宣传。展望未来，它将把人力资源开发努力与TU-Teach等现有项目相结合，这些项目使本科生和当地高中理科教师受益。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毕业生已被行业聘用，并进入学术界的终身教职轨道，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.