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） 标题为“具有成本效益，协同的大分子结构确定，分析和模拟”，这 建议涉及生物学核心的系统：CCT真核生物伴侣蛋白，RNA聚合酶II和 核糖体，我们的所有同事都在实验研究。我们将开发公正的方法 用更少的数据解决结构。对分子机在运行时的移动感兴趣，我们映射出来 使用多尺度混合方法的状态空间。我们所有的方法和策划数据将被传播 自由。这些项目是及时的，因为这些大分子机器具有关键的细胞功能。工具 我们开发确定结构，分析和模拟将有助于其他人推进生物医学。 首席研究员迈克尔·莱维特（Michael Levitt）从事独立科学研究的漫长职业生涯 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结构改进，结构分析和计算框架的理论和计算框架 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，他一直在富有成效，科学严格和影响力。特别 创新是他在过去五年中的工作，导致了两者都可以解决生物医学意义的原始方法 结构并模拟功能运动。这些领域通过致力于心理的PI继续 年轻的科学家以及参与持续的研究社区服务和公共宣传。 1。开发新颖的方法来确定和完善大分子复合物。这 第一个亚地区将处理确定氨基酸侧链的身份。第二个亚地区将 涉及一种新方法来自动结构确定，不需要手动干预。两个都 方法将适用于冷冻EM电子密度图。 2。开发新的方法来分析结构。第一个子地区将处理 结构策划。对于核糖体工作至关重要，随着结构积累，它将越来越有用 其他大分子复合物。第二个亚地区的重点是寻找反应途径的方法 来自此类复合物的多个结构。第三个子区域将测试并开发新方法 结构变形几乎没有自由度。第四次区域将使用熔融区分子 研究功能运动的动力学。 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 将确定关键状态，在这些状态之间变体以找到反应路径并运行分子动力学。 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 引人入胜的生物学细节。这项工作将阐明结构与 在大型大分子机器中发挥作用，这是现代生物医学科学的基石。