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共同资助。它是根据信息技术研究招标NSF-04-012提交给材料研究部的提案制定的。该奖项涵盖的研究活动属于国家优先领域“科学与工程进展”和技术重点领域“计算建模或模拟研究中的创新”。该奖项支持计算研究和教育，以开发模拟方法，并使用它们来阐明伴侣蛋白在蛋白质折叠中的作用。近十年来，伴侣蛋白已成为研究最活跃的一类生物分子。对它们如何在活细胞中协助蛋白质折叠的详细了解，将为优化表达所需多肽的工程细胞提供机会，甚至可以设计药物来对抗由蛋白质药物引起的疾病。该项目涉及大规模分子模拟，以回答有关大肠杆菌GroEL/GroES伴侣蛋白复合物协助蛋白质折叠的机制的具体问题。过渡路径采样蒙特卡罗（TPS）将与新的非均匀分辨率描述相结合，使用最少的详细信息作为输入，实现对速率和机制的统计有效预测。在非均匀分子模拟范例中，区域被分为(i)一个或多个感兴趣的原子分解区域，以及（ii）一个更大的周围系统粗化的子区域。粗化的描述减少了对原子解析系统的计算工作量，而感兴趣的区域表示系统的特异性达到所需的水平。该项目有两个大的阶段，致力于回答以下问题：(1)与GroEL的结合是否与错误折叠蛋白质的二级和三级结构的破坏有关？(2) GroEL在转化为活性态时，与大规模构象变化相关的本征能垒是什么？这项工作的广泛影响包括：为生物物理学研究生课程开发伴侣蛋白辅助蛋白质折叠课程模块；开设研究生水平的分子模拟课程，该课程将纳入系统分子粗粒化的主要新技术；？让本科生参与研究，着眼于纳入代表性不足的群体；并举办演讲准备和演讲技巧的研讨会，主要是为了让学生受益。本项目的本科生和研究生研究人员将被鼓励在国家会议上展示他们的工作。该奖项由材料研究部和化学部共同资助。它是根据信息技术研究招标NSF-04-012提交给材料研究部的提案制定的。该奖项涵盖的研究活动属于国家优先领域“科学与工程进展”和技术重点领域“计算建模或模拟研究中的创新”。该奖项支持与生物学相结合的计算研究和教育。PI将以一种创新的方式使用大规模模拟技术来研究被称为伴侣蛋白的生物分子在长链状蛋白质分子自我折叠以实现实现特定生化功能的原子配置的过程中的作用。近十年来，伴侣蛋白已成为研究最活跃的一类生物分子。对它们在活细胞中协助蛋白质折叠的详细了解，将为优化表达所需多肽的工程细胞提供机会，甚至可以设计药物来对抗由蛋白质药物引起的疾病。PI将使用模拟技术来关注有关大肠杆菌GroEL/GroES伴侣蛋白复合物协助蛋白质折叠的机制的具体问题。这项工作的广泛影响包括：为生物物理学研究生课程开发伴侣蛋白辅助蛋白质折叠课程模块；开设研究生水平的分子模拟课程，该课程将纳入系统分子粗粒化的主要新技术；？让本科生参与研究，着眼于纳入代表性不足的群体；并举办演讲准备和演讲技巧的研讨会，主要是为了让学生受益。本项目的本科生和研究生研究人员将被鼓励在国家会议上展示他们的工作。＊＊＊