Modeling and dynamics of biomolecules on cellular scales

细胞尺度上生物分子的建模和动力学

• 批准号: 9484503
• 负责人: Michael Feig
• 金额: $ 32.71万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9484503
• 关键词: Affect; Biochemistry; Biological; Biological Process; Biology; Cells; Communities; Complex; Computer Simulation; Computer software; Crowding; DNA; DNA Repair; DNA-Directed RNA Polymerase; Data; Development; Disease; Drug Design; Environment; Functional disorder; Genetic Transcription; Malignant Neoplasms; Membrane Proteins; Methods; Mismatch Repair; Modeling; Molecular; Molecular Biology; Nucleic Acids; Play; Proteins; Research; Resolution; Structure; Systems Biology; Therapeutic Intervention; improved; molecular dynamics; molecular scale; protein structure; restraint; single molecule; structural biology; targeted treatment

PROJECT SUMMARY Understanding biology and disease requires a full connection from molecular scales, at which the fundamental biochemistry takes place, to cellular scales, where biological function (or dysfunction) is realized. Structural and molecular biology have long-focused on the molecular levels whereas systems biology emphasizes the cellular scale. The key challenge is now how to connect between these scales to gain a comprehensive understanding of complex diseases and pave the way to rational drug design at the whole-cell level. Computer simulations play a key role in this effort as they allow the modeling of biomolecules at different scales and the subsequent study of their dynamics to connect structure with function. The Feig lab focuses on the development and application of molecular dynamics and multi- scale methods for the high-resolution modeling of proteins and nucleic acids, the mechanistic analysis of fundamental biological processes such as transcription and DNA repair, and studies of biomolecules under crowded cellular environments. Future research focuses on improving protein structure refinement methods to achieve near-experimental accuracy, either de novo or in combination with high-resolution cryo EM data, improve the prediction of membrane protein structures, and develop methods for the high- resolution modeling of chromosomal DNA using experimental restraints from Hi-C data. Mechanistic studies of transcription by RNA polymerase and DNA mismatch repair initiation by MutS will be expanded to more realistic biological contexts and studies of crowded cellular environments will be continued to understand how single molecule dynamics and function is affected by the cellular environment. Finally, multi-scale methods that can bridge from molecular to cellular scales will be developed and implemented in community software.

项目概要 了解生物学和疾病需要从分子尺度上充分联系起来， 基本的生物化学发生在细胞尺度上，其中生物功能（或功能障碍）是 意识到了。结构生物学和分子生物学长期以来一直关注分子水平，而系统生物学 生物学强调细胞尺度。现在的关键挑战是如何在这些尺度之间建立联系 全面了解复杂疾病，为合理药物设计铺平道路 在全细胞水平。计算机模拟在这项工作中发挥着关键作用，因为它们允许对 不同尺度的生物分子及其随后的动力学研究，以将结构与 功能。 Feig实验室专注于分子动力学和多学科的发展和应用 蛋白质和核酸高分辨率建模的尺度方法、机制分析 转录和 DNA 修复等基本生物过程以及生物分子研究 在拥挤的蜂窝环境下。未来的研究重点是改善蛋白质结构的细化 达到接近实验精度的方法，无论是从头开始还是与高分辨率相结合 冷冻电镜数据，改进膜蛋白结构的预测，并开发高通量方法 使用 Hi-C 数据的实验限制对染色体 DNA 进行分辨率建模。机械论 RNA聚合酶转录和MutS启动DNA错配修复的研究将得到扩展 将继续对更现实的生物环境和拥挤的细胞环境进行研究 了解单分子动力学和功能如何受到细胞环境的影响。最后， 将开发和实施可以从分子尺度到细胞尺度的多尺度方法 在社区软件中。