Collaborative Research: Multiscale molecular simulations of protein-mediated bilayer fusion

合作研究：蛋白质介导的双层融合的多尺度分子模拟

• 批准号: 1330205
• 负责人: Cameron Abrams
• 金额: $ 35.09万
• 依托单位: Drexel University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-15 至 2018-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1330205&HistoricalAwards=false
• 关键词: Collaborative; Research; Multiscale; molecular; simulations

INTELLECTUAL MERITPerhaps the most important structure for cellular life as we know it is the lipid bilayer. Lipid molecules, consisting of a water-soluble "head" and water-insoluble "tails", spontaneously assemble into sandwich-like bilayer membranes, which surround all living cells and further compartmentalize the cellular interiors of all eukaryotic organisms the domain of life to which plants, fungi, animals, and humans belong. The network of membranes in a typical eukaryotic cell is very complex and highly dynamic: small compartments bud off from certain membranes like bubbles, carrying cargo from one part of the cell to another, where they can fuse with yet other membranes, including the outer membrane of the cell. Bilayer fusion is therefore a ubiquitous biological process, tightly linked to the transport of material and information, and therefore it is exquisitely controlled by several classes of membrane-associated proteins. These proteins clearly perform work on the fusing membranes, but the intricate sequence of geometric and topological shape transformations they induce on the molecular scale are impossible to observe directly in experiment. In contrast, molecular simulation offers a window onto these details, but until now the relevant length- and time-scales have proven too big to observe even a single fusion event for a realistic system size. This project establishes a collaboration between two investigators with the aim to meet this challenge by combining recent advances in multiscale coarse-grained modeling with enhanced-sampling molecular simulation. Since this strategy allows incorporating important chemical detail while simultaneously representing large-scale membrane deformations, the investigators will be able to elucidate how molecular-level mechanisms drive fusion events across the relevant physiological length- and time-scales. The project proceeds through three phases, namely: (i) modeling the fusion of pristine bilayers with enhanced sampling, (ii) development of coarse-grained models of model fusogenic proteins, the SNARE system, and (iii) combining these two steps into a single methodology. The project will pursue many topics of energetic, morphological, and mechanistic relevance, in particular questions revolving around the so-called hemifusion intermediate state, for which the two outer bilayer leaflets have already fused but a membrane formed by the two inner leaflets still separates the two compartments.BROADER IMPACTSThis project will impact many topics in the biological sciences due to the central importance of bilayer fusion in a variety of biological processes, including intracellular trafficking, viral entry, neurotransmitter release, fertilization, and more. Beyond the specific questions under study, the computational approach envisioned here takes early steps towards efficient simulation of more complicated multiple-protein/multiple-membrane phenomena and will therefore benefit future studies of a wider class of molecular biological topics. To broaden applicability of the research outcomes, the simulation framework developed in this project will be made freely available with tutorials that will support efficient learning and facilitate the transformation of existing techniques and modules towards novel applications. This project establishes cross-disciplinary exchange between engineering and (bio)physics, fostering a stimulating interdisciplinary environment for the academic growth of students mentored in this project. It will further the transfer of theoretical and computational methodologies from engineering and physics into the life sciences and their increasingly quantitative set of problems. The ubiquity of bilayer fusion and its connection to a wide class of fascinating themes in biological physics, which is in itself an intriguing cross-disciplinary subject, also present excellent opportunities for the expertise developed in this project to feed outreach specifically tailored towards groups underrepresented in STEM fields for instance through classroom material, lecture demonstrations, and public talks and both investigators will implement such activities, building on both their experience and existing successful programs at their respective institutions.

智力优点也许是我们所知道的是脂质双层的最重要结构。脂质分子由水溶性的“头”和不溶于水的“尾巴”组成，自发地组装成三明治的双层膜，它们围绕着所有活细胞，并进一步将所有真核生物的蜂窝室内植物与所有真实性生物的植物域的植物，植物，fungi，fungi属于动物，动物，动物和人类属于生命。典型的真核细胞中的膜网络非常复杂且高度动态：小室从某些膜从某些膜（如气泡）芽，将货物从细胞的一个部分带到另一部分，它们可以与其他膜融合，包括细胞的外膜。因此，双层融合是一种无处不在的生物学过程，与材料和信息的运输密切相关，因此由几类与膜相关的蛋白质精制控制。这些蛋白质清楚地在融合膜上进行了工作，但是在实验中无法直接观察到它们在分子尺度上诱导的几何和拓扑形状转化的复杂序列。相比之下，分子模拟为这些细节提供了一个窗口，但是直到现在，相关的长度和时间尺度已被证明太大了，甚至无法观察到一个逼真的系统大小。该项目建立了两名研究人员之间的合作，目的是通过将多尺度粗粒建模的最新进展与增强的分子模拟结合在一起来应对这一挑战。由于该策略允许合并重要的化学细节，同时代表大规模膜变形，因此研究人员将能够阐明分子级机制如何在相关生理长度和时间尺度上驱动融合事件。该项目通过三个阶段进行，即：（i）对原始双层的融合进行建模，以增强的采样，（ii）开发模型官基因蛋白的粗粒模型，SNARE系统，以及（iii）将这两个步骤组合到单个方法论中。该项目将追求许多充满活力，形态学和机械性相关性的主题，特别是围绕所谓的下半部置换中间状态循环的问题，在该状态下，两个外部双层传单已经融合在一起，但两个内部传单形成的膜仍将两个内部传单造成了两个内部的传单，但仍将两种障碍物分开。生物过程，包括细胞内贩运，病毒进入，神经递质释放，受精等。除了研究的具体问题外，这里设想的计算方法还采取了早期步骤，以有效地模拟更复杂的多蛋白/多膜现象，因此将使对更广泛的分子生物学主题的未来研究有益。为了扩大研究成果的适用性，该项目中开发的仿真框架将通过教程免费提供，这些教程将支持有效的学习并促进现有技术和模块向新应用的转换。该项目建立了工程和（生物）物理学之间的跨学科交流，为该项目指导的学生的学术增长促进了令人兴奋的跨学科环境。它将进一步将理论和计算方法从工程和物理学转移到生命科学及其日益定量的问题集。双层融合的无处不在及其与生物物理学中的广泛引人入胜的主题的联系，这本身就是一个有趣的跨学科主题，这也为该项目提供了极好的机会，可以在该项目中开发出的专业知识，旨在通过在课堂材料，讲座的示范和公共场合中实施的活动，以及在STEM中专门量身定制的范围，并在课堂上，讲座示范，讲座的示范，讲座，并为他们提供了各种活动，并在课堂上实施了这些活动，这些活动的示范，讲座示范，讲座示范，讲座，并为他们提供了研究，并在课堂上，讲座，讲座示范，讲座，并为他们提供了研究，并为他们提供了研究。机构。