Cost Effective, Synergistic Macromolecular Structure Determination, Analysis & Simulation

成本有效、协同的大分子结构测定、分析

• 批准号: 10016355
• 负责人: MICHAEL LEVITT
• 金额: $ 56.79万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10016355
• 关键词: Amino Acids; Area; Biology; Cell physiology; Collaborations; Community Services; Complex; Computational Biology; Cryoelectron Microscopy; DNA Polymerase II; DNA Structure; Data; Development; Eukaryota; Freedom; Heart; Hybrids; Intervention; Macromolecular Complexes; Manuals; Maps; Mentors; Methods; Modernization; Molecular Conformation; Molecular Machines; Molecular Structure; Motion; Movement; Pathway Analysis; Pathway interactions; Principal Investigator; RNA; RNA Polymerase II; Reaction; Research; Ribosomes; Running; Science; Scientist; Side; Structure; System; Testing; Time; Work; career; chaperonin; computer code; computer framework; cost effective; electron density; experimental study; fascinate; innovation; interest; molecular dynamics; novel strategies; outreach; protein structure; simulation; software development; tool

Project Summary (30 lines) Entitled “Cost Effective, Synergistic Macromolecular Structure Determination, Analysis & Simulation”, this proposal involves systems at the heart of biology: CCT Eukaryote Chaperonin, RNA Polymerase II, and the Ribosome, all of which our colleagues are studying experimentally. We will develop unbiased methods to solve structures with less data. Interested in how molecular machines move as they function, we map out their state-space using multi-scale hybrid methods. All our methods and curated data will be disseminated freely. This project is timely as these macromolecular machines carry out key cellular functions. The tools we develop for structure determination, analysis and simulation will aid others in advancing biomedicine. Michael Levitt, the Principal Investigator has a long career of independent scientific research that started in 1967 when he was one of the first to work in computational biology. His early work set up the conceptual, theoretical and computational framework for protein and DNA structure refinement, structure analysis and macromolecular simulations. He makes computer codes available and continues hands-on software development. He has been productive, scientifically rigorous and impactful for half a century. Particularly innovative is his work for the past five years leading to original methods to both solve biomedically significant structures and simulate functional motion. These areas are continued here by a PI committed to mentoring young scientists as well as engaging in sustained research-community service and public outreach. 1. Develop Novel Approaches to Determination and Refinement of Macromolecular Complexes. The first sub-area will deal with determining the identity of amino acid side chains. The second sub-area will involve a new approach to automatic structure determination requiring no manual intervention. Both methods will be adapted to cryo-EM electron density maps. 2. Develop Novel Approaches to Pathway Analysis of Structures. The first sub-area will deal with structure curation. Essential for ribosome work, it will be increasingly useful as structures accumulate for other macromolecular complexes. The second sub-area focuses on methods to find reaction pathways from multiple structures of such complexes. The third sub-area will test and develop new methods for structure morphing with few degrees of freedom. The forth sub-area will use Molten Zone molecular dynamics to study functional movement. 3. Determine the State-Space of Functional Motion in Chaperonin, RNA Pol II, and the Ribosome. We will identify key states, morph between these states to find reaction paths and run molecular dynamics. Studying these biomedically significant systems in collaboration with experimental colleagues will reveal fascinating details of biology in action. This work will elucidate the relationship between structure and function in large macromolecular machines, a keystone of modern biomedical science.

项目摘要（30行） 题为“成本效益，协同大分子结构测定，分析和模拟”，这 该提案涉及生物学核心系统：CCT真核细胞伴侣蛋白，RNA聚合酶II和 核糖体，我们的同事正在对所有这些进行实验研究。我们将开发无偏见的方法， 用更少的数据解决结构问题。对分子机器如何运作感兴趣，我们绘制了 它们的状态空间使用多尺度混合方法。我们所有的方法和策划数据将被传播 自由.这个项目是及时的，因为这些大分子机器执行关键的细胞功能。的工具 我们开发的结构测定、分析和模拟技术将帮助其他人推进生物医学。 首席研究员迈克尔·莱维特（Michael Levitt）有着长期的独立科学研究生涯， 1967年，他是最早从事计算生物学工作的人之一。他的早期工作建立了概念， 蛋白质和DNA结构精修、结构分析和 大分子模拟他使计算机代码可用，并继续动手软件 发展半个世纪来，他一直富有成效，科学严谨，影响深远。特别 创新是他在过去五年的工作，导致原始方法，以解决生物医学意义 结构和模拟功能运动。这些领域在这里继续由PI致力于指导 青年科学家以及从事持续的研究-社区服务和公共宣传。 1.开发新的方法来测定和精制高分子复合物。的 第一个子区域将处理确定氨基酸侧链的同一性。第二个分区将 涉及不需要人工干预自动结构确定的新方法。两 方法将适用于冷冻EM电子密度图。 2.开发新的结构通路分析方法。第一个分区域将处理 结构策展。对于核糖体工作至关重要，随着结构的积累， 其他高分子复合物。第二个子领域侧重于寻找反应途径的方法 这类复合物的多种结构。第三个分区域将测试和开发新的方法， 结构变形的自由度很小。第四个分区将使用熔融区分子 动力学来研究功能性运动。 3.确定伴侣蛋白，RNA Pol II和核糖体中功能运动的状态空间。我们 将识别关键状态，这些状态之间的变形，以找到反应路径和运行分子动力学。 与实验同事合作研究这些具有生物医学意义的系统将揭示 有趣的生物学细节这项工作将阐明结构和 功能的大型高分子机器，现代生物医学科学的基石。