ITR-ASE-Sim: Inhomogeneously Resolved Simulation of Protein Assembly Dynamics

ITR-ASE-Sim：蛋白质组装动力学的非均匀解析模拟

• 批准号: 0427643
• 负责人: Cameron Abrams
• 金额: $ 42万
• 依托单位: Drexel University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-01 至 2010-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0427643&HistoricalAwards=false
• 关键词: ITR; ASE; Sim; Inhomogeneously; Resolved

This award is cofunded by the Division of Materials Research and the Chemistry Division. It was made on a proposal submitted to the Division of Materials Research under the Information Technology Research solicitation NSF-04-012. Research activities covered by this award fall under the National Priority Area, "Advances in Science and Engineering," and the Technical Focus Area, "Innovation in Computational Modeling or Simulation in Research." This award supports computational research and education to develop simulation methods and use them to elucidate the role of chaperonins in protein folding.In the last ten years, chaperonins have become one of the most actively studied classes of biomolecules. A detailed understanding of how they assist protein folding in living cells will enable opportunities for engineering cells for optimal expression of desired polypeptides and even designing agents to combat diseases caused by protein agents. This project involves large-scale molecular simulation to answer specific questions regarding the mechanisms by which the E. Coli GroEL/GroES chaperonin protein complex assists the folding of proteins. Transition path sampling Monte-Carlo (TPS) will be combined with new inhomogeneous resolution descriptions to enable statistically valid predictions of rates and mechanisms using a minimum of detailed information as input. In the paradigm of inhomogeneous molecular simulation, the domain is divided into (i) one or more atomically resolved regions of interest, and (ii) a much larger surrounding systematically coarsened subdomain. The coarsened descriptions reduce the computational effort over atomically resolved systems, while the regions of interest represent the system's specificity up to a desired level. The project has two broad phases, devoted to answering the questions: (1) Is binding to GroEL correlated with the destruction of secondary and tertiary structure in misfolded proteins? (2) What are the intrinsic energy barriers associated with large-scale conformational changes of GroEL upon conversion to its active state? The broader impacts of this work include: developing a course module on chaperonin-assisted protein folding for a graduate course in biological physics; developing a graduate level course on molecular simulation which will incorporate major new techniques of systematic molecular coarse graining; ?involving undergraduates in research recruited with an eye to including underrepresented groups; and conducting workshops on presentation preparation and delivery skills, primarily to benefit students. Undergraduate and graduate student researchers on this project will be encouraged to present their work at national conferences. %%%This award is cofunded by the Division of Materials Research and the Chemistry Division. It was made on a proposal submitted to the Division of Materials Research under the Information Technology Research solicitation NSF-04-012. Research activities covered by this award fall under the National Priority Area, "Advances in Science and Engineering," and the Technical Focus Area, "Innovation in Computational Modeling or Simulation in Research." This award supports computational research and education at the interface with biology. The PI will use large-scale simulation techniques in an innovative way to study the role of biomolecules known as chaperonins in the process whereby long chain-like protein molecules fold on themselves to achieve a configuration of atoms that enables specific biochemical functions. In the last ten years, chaperonins have become one of the most actively studied classes of biomolecules. A detailed understanding of they assist protein folding in living cells will enable opportunities for engineering cells for optimal expression of desired polypeptides and even designing agents to combat diseases caused by protein agents. The PI will use simulation techniques to focus on specific issues regarding the mechanisms by which the E. Coli GroEL/GroES chaperonin protein complex assists the folding of proteins. The broader impacts of this work include: developing a course module on chaperonin-assisted protein folding for a graduate course in biological physics; developing a graduate level course on molecular simulation which will incorporate major new techniques of systematic molecular coarse graining; ?involving undergraduates in research recruited with an eye to including underrepresented groups; and conducting workshops on presentation preparation and delivery skills, primarily to benefit students. Undergraduate and graduate student researchers on this project will be encouraged to present their work at national conferences. ***

该奖项由材料研究部和化学部授予地带。它是根据信息技术研究邀请NSF-04-012提交给材料研究部的提案。该奖项涵盖的研究活动属于国家优先领域，“科学与工程学的进步”以及技术重点领域，“计算建模或研究中的仿真创新”。该奖项支持计算研究和教育，以开发仿真方法，并使用它们来阐明伴侣蛋白在蛋白质折叠中的作用。在过去的十年中，伴侣蛋白已成为研究最积极的生物分子类别之一。对它们如何帮助活细胞中蛋白质折叠的详细理解将使工程细胞最佳表达所需的多肽，甚至设计剂以打击由蛋白质剂引起的疾病。 该项目涉及大规模的分子模拟，以回答有关大肠杆菌/凹槽/凹槽伴侣蛋白蛋白复合物有助于蛋白质折叠的机制的特定问题。 过渡路径采样蒙特卡洛（TPS）将与新的不均匀分辨率描述结合使用，以使用最少的详细信息作为输入来启用统计上有效的费率和机制的预测。 在不均匀分子模拟的范式中，该结构域分为（i）一个或多个原子解析的感兴趣区域，以及（ii）周围系统块状的子域更大。 精巧的描述减少了原子解决系统上的计算工作，而感兴趣的区域则代表系统的特异性，直至所需的水平。 该项目有两个广泛的阶段，致力于回答问题：（1）与凹槽的结合与错误折叠的蛋白质中的二级和三级结构的破坏相关？ （2）在转化为活跃状态时，与大规模构象变化有关的内在能屏障是什么？这项工作的更广泛影响包括：为伴侣蛋白辅助蛋白质折叠开发一个课程模块，以促进生物物理学研究生课程；开发有关分子模拟的研究生水平课程，该课程将结合系统的系统分子粗网技术；涉及本科生参与研究的招募，以关注包括代表性不足的群体；并开展有关演讲准备和交付技巧的讲习班，主要是为了使学生受益。该项目的本科生和研究生研究人员将鼓励在国家会议上介绍他们的作品。 %% %%该奖项由材料研究部和化学部的分支机构。它是根据信息技术研究邀请NSF-04-012提交给材料研究部的提案。该奖项涵盖的研究活动属于国家优先领域，“科学与工程学的进步”以及技术重点领域，“计算建模或研究中的仿真创新”。该奖项支持与生物学界面上的计算研究和教育。 PI将以创新的方式使用大规模的模拟技术来研究称为伴侣蛋白的生物分子在此过程中的作用，从而使长链样蛋白质分子折叠自身以实现原子的构型，从而实现特定的生化功能。在过去的十年中，伴侣蛋白已成为研究最积极的生物分子类别之一。对它们有助于活细胞中蛋白质折叠的详细理解将为工程细胞提供最佳表达所需多肽的表达机会，甚至设计剂以打击由蛋白质剂引起的疾病。 PI将使用仿真技术专注于有关大肠杆菌/凹槽/凹槽伴侣蛋白蛋白复合物有助于蛋白质折叠的机制的特定问题。 这项工作的更广泛影响包括：为伴侣蛋白辅助蛋白质折叠开发一个课程模块，以促进生物物理学研究生课程；开发有关分子模拟的研究生水平课程，该课程将结合系统的系统分子粗网技术；涉及本科生参与研究的招募，以关注包括代表性不足的群体；并开展有关演讲准备和交付技巧的讲习班，主要是为了使学生受益。该项目的本科生和研究生研究人员将鼓励在国家会议上介绍他们的作品。 ***