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: 10364749
• 负责人: Michael Feig
• 金额: $ 37.74万
• 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 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10364749
• 关键词: Affect; Biochemistry; Biological; Biological Process; Biology; Cells; Communities; Complex; Computer Simulation; Computer software; Crowding; Cryoelectron Microscopy; DNA; DNA Repair; DNA-Directed RNA Polymerase; Data; Development; Disease; Drug Design; Environment; Functional disorder; Genetic Transcription; Hi-C; 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 理解生物学和疾病需要从分子尺度上完全联系起来，在分子尺度上， 基本的生物化学发生在细胞尺度上，生物功能（或功能障碍） 实现了结构和分子生物学长期以来一直专注于分子水平，而系统 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，为合理设计药物铺平道路 在整个细胞水平上。计算机模拟在这一努力中发挥着关键作用，因为它们可以模拟 生物分子在不同的尺度和随后的研究，他们的动态连接结构与 功能Feig实验室专注于分子动力学和多分子动力学的发展和应用。 蛋白质和核酸的高分辨率建模的尺度方法， 基本的生物过程，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。未来的研究重点是提高蛋白质结构的精细化 方法，以实现接近实验的准确性，无论是从头或结合高分辨率 冷冻EM数据，提高膜蛋白结构的预测，并开发用于高- 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聚合酶的转录和MutS启动DNA错配修复的研究将得到扩展 到更现实的生物背景和拥挤的细胞环境的研究将继续， 了解单分子动力学和功能如何受到细胞环境的影响。最后， 将开发和实施从分子尺度到细胞尺度的多尺度方法 社区软件。

项目成果

Improved Sampling Strategies for Protein Model Refinement Based on Molecular Dynamics Simulation.

• DOI: 10.1021/acs.jctc.0c01238
• 发表时间: 2021-03-09
• 期刊: Journal of chemical theory and computation
• 影响因子: 5.5
• 作者: Heo L;Arbour CF;Janson G;Feig M
• 通讯作者: Feig M

Direct generation of protein conformational ensembles via machine learning.

• DOI: 10.1038/s41467-023-36443-x
• 发表时间: 2023-02-11
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Janson, Giacomo;Valdes-Garcia, Gilberto;Heo, Lim;Feig, Michael
• 通讯作者: Feig, Michael

Characterization of RNA polymerase II trigger loop mutations using molecular dynamics simulations and machine learning.

• DOI: 10.1371/journal.pcbi.1010999
• 发表时间: 2023-03
• 期刊: PLoS computational biology
• 影响因子: 4.3

New parallel computing algorithm of molecular dynamics for extremely huge scale biological systems.

• DOI: 10.1002/jcc.26450
• 发表时间: 2021-02-05
• 期刊: Journal of computational chemistry
• 影响因子: 3
• 作者: Jung J;Kobayashi C;Kasahara K;Tan C;Kuroda A;Minami K;Ishiduki S;Nishiki T;Inoue H;Ishikawa Y;Feig M;Sugita Y
• 通讯作者: Sugita Y

Intramolecular Diffusion in α-Synuclein: It Depends on How You Measure It.

α-突触核蛋白的分子内扩散：这取决于您如何测量它。

• DOI: 10.1016/j.bpj.2018.08.023
• 发表时间: 2018
• 期刊: Biophysical journal
• 影响因子: 3.4
• 作者: Woodard,Jaie;Srivastava,KinshukR;Rahamim,Gil;Grupi,Asaf;Hogan,Steven;Witalka,DavidJ;Nawrocki,Grzegorz;Haas,Elisha;Feig,Michael;Lapidus,LisaJ
• 通讯作者: Lapidus,LisaJ