EAGER: Bio-Mimetic Molecular Machines Driven by Brownian Motion of Synthetic Peptoid Polymers

EAGER：由合成类肽聚合物的布朗运动驱动的仿生分子机器

• 批准号: 1733575
• 负责人: Markita Landry
• 金额: $ 13万
• 依托单位: University of California-Berkeley
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-01-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1733575&HistoricalAwards=false
• 关键词: EAGER; Bio; Mimetic; Molecular; Machines

Proteins form the core arsenal of life, in signaling how living organisms behave, grow, and interact with their environment. To accomplish this range of biological functions, proteins have evolved remarkable attributes to interact specifically with other proteins, or with DNA. Recent discoveries have shown that certain conserved protein sequences have evolved the ability to "walk" along DNA in search of their target sites to enable this site-specific activity. The extraordinary speed and precision with which proteins accomplish this task remains a mystery, one that could have many benefits for engineering if the molecular precision of protein-DNA interactions could be reproduced in nanoscale synthetic systems. The research team will synthesize and characterize novel nanoscale materials that will behave like natural proteins in their ability to "walk" along DNA. This work could enable better understanding of how to design enzymes for bio-energy applications, antibodies for biological nanosensors, and protein-DNA interactions that drive all underlying cell processes. As a core component of the proposed research, the primary investigator will collaborate with Society for the Advancement of Chicanos and Native Americans in Science program at UC Berkeley to recruit two undergraduate students representing minority communities to the primary investigator's lab.Brownian 1D diffusion of proteins along DNA enables protein-mediated cellular processes to occur on biologically-relevant timescales. Recent discoveries in protein biophysics have identified conserved sequences to facilitate 1-dimensional Brownian motion along DNA to expedite the target search process to a biologically-relevant timescale. Synthetic nanostructures have not been well-explored as bio-mimetic tools. Now that the "blueprints" for 1-dimensional Brownian diffusion are less elusive, the investigators propose an orthogonal study to apply these blueprints from biophysics to bioengineering. Here, the investigators seek to exploit these evolved features of site-specific proteins' 1-dimensional diffusion along DNA to build synthetic peptoid-based molecular machines. To-date, the study of synthetic motors has relied on the input of external sources of energy (chemical, photonic, etc). The investigators seek to exploit random (Brownian) mobility as a tool to build molecular translocators from synthetic bio-mimetic structures. Ultimately, the prediction is that the synthetic "Brownian machines" might carry molecular cargo, of potential applicability to fundamental and applied molecular and cellular research alike. This project combines high- resolution single-molecule fluorescence microscopy with robotic peptoid synthesis to develop a new class of synthetic materials capable of exploiting electrostatics for synthetic molecular machines. This work could be akin to the proof-of-principle exploratory research in scaffold-and-staple DNA-assembly that led to the field of DNA Origami. As a member of the underrepresented scientist community, the PI is both a strong supporter, and active leader in organizations supporting underrepresented scientists. This research effort will be integrated with the UC Berkeley Latino/a American Graduate Students in Engineering and Science program at Berkeley, and the Society for the Advancement of Chicanos and Native Americans. Prof. Landry will also organize and host the first nanobiosciences conference in Cuba, in collaboration with Prof. Dionisio Zaldivar Silva, Dean of the Faculty of Chemistry at the University of Havana Cuba. This NanoMEDD conference in Havana will be held using extramural funding that has already been secured.

蛋白质构成了生命的核心武器库，它发出生物体如何行为、生长以及与环境相互作用的信号。为了实现这一系列的生物学功能，蛋白质已经进化出与其他蛋白质或DNA特异性相互作用的显著属性。最近的发现表明，某些保守的蛋白质序列已经进化出沿着DNA“行走”沿着寻找其靶位点的能力，以实现这种位点特异性活性。 蛋白质完成这一任务的非凡速度和精度仍然是一个谜，如果蛋白质-DNA相互作用的分子精度可以在纳米级合成系统中重现，那么它可能对工程有很多好处。该研究小组将合成和表征新型纳米材料，这些材料在沿着DNA“行走”的能力方面表现得像天然蛋白质。这项工作可以更好地理解如何设计用于生物能源应用的酶，用于生物纳米传感器的抗体，以及驱动所有潜在细胞过程的蛋白质-DNA相互作用。作为拟议研究的核心组成部分，主要研究者将与加州大学伯克利分校的科学计划中的奇卡诺人和美洲原住民促进协会合作，招募两名代表少数民族社区的本科生到主要研究者的实验室。蛋白质沿着DNA的布朗一维扩散使蛋白质介导的细胞过程在生物相关的时间尺度上发生。蛋白质生物物理学的最新发现已经确定了保守序列，以促进沿沿着DNA的一维布朗运动，从而将目标搜索过程加速到生物学相关的时间尺度。合成纳米结构还没有被很好地探索作为生物模拟工具。既然一维布朗扩散的“蓝图”不再那么难以捉摸，研究人员提出了一种正交研究，将这些蓝图从生物物理学应用到生物工程学中。在这里，研究人员试图利用位点特异性蛋白质沿着DNA一维扩散的这些进化特征来构建基于合成肽的分子机器。迄今为止，合成马达的研究依赖于外部能源（化学，光子等）的输入。研究人员试图利用随机（布朗）流动性作为一种工具，从合成的仿生结构中构建分子移位器。最终，预测是合成的“布朗机器”可能携带分子货物，对基础和应用分子和细胞研究具有潜在的适用性。该项目将高分辨率单分子荧光显微镜与机器人类肽合成相结合，以开发一类能够利用静电用于合成分子机器的新型合成材料。这项工作可能类似于支架和钉合DNA组装的原理验证探索性研究，该研究导致了DNA折纸领域。作为代表性不足的科学家社区的一员，PI既是一个强有力的支持者，也是支持代表性不足的科学家的组织的积极领导者。这项研究工作将与加州大学伯克利分校拉丁裔/美国研究生在工程和科学计划在伯克利分校，并为奇卡诺斯和美洲原住民的进步社会整合。Landry教授还将与古巴哈瓦那大学化学系主任Dionisio Zaldivar Silva教授合作，组织和主办古巴第一届纳米生物科学会议。这次在哈瓦那举行的NanoMEDD会议将使用已经获得的校外资金。