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.

项目摘要 了解生物学和疾病需要与分子量表完全联系 基本的生物化学发生在生物学功能（或功能障碍）为的细胞量表上 实现。结构和分子生物学已长期集中在分子水平上，而系统 生物学强调细胞量表。关键挑战现在如何在这些量表之间连接 要全面了解复杂疾病，并为理性药物设计铺平了道路 在整个细胞级别。计算机模拟在这项工作中起着关键作用，因为它们允许建模 在不同尺度的生物分子以及随后对其动力学的研究，以将结构与 功能。 FEIG实验室的重点是分子动力学的开发和应用 蛋白质和核酸高分辨率建模的比例方法，机械分析 基本生物学过程，例如转录和DNA修复以及生物分子的研究 在拥挤的细胞环境下。未来的研究重点是改善蛋白质结构的完善 从头开始或与高分辨率结合的方法 冷冻数据，改善膜蛋白结构的预测，并开发高级方法 使用HI-C数据的实验限制对染色体DNA的分辨率建模。机理 RNA聚合酶和DNA不匹配修复开始的转录研究将扩大 对于更现实的生物学环境和对拥挤的细胞环境的研究将继续进行 了解单个分子动力学和功能如何受细胞环境的影响。最后， 将开发和实现可以从分子到细胞尺度桥接的多尺度方法 在社区软件中。