Modeling and dynamics of biomolecules on cellular scales

项目总结 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 基础生物化学发生在细胞尺度上，生物功能(或功能障碍)是 意识到了。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规模之间建立联系 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与结构关联的动力学研究 功能。Feig实验室专注于分子动力学和多学科的发展和应用。 蛋白质和核酸的高分辨率模拟的尺度方法，其机理分析 基本生物学过程，如转录和DNA修复以及生物分子研究 在拥挤的蜂窝环境下。未来的研究重点是提高蛋白质结构的精细化 获得接近实验精度的方法，要么从头开始，要么结合高分辨率 冷冻EM数据，改进膜蛋白结构的预测，并开发高密度脂蛋白的方法。 利用Hi-C数据的实验约束对染色体DNA进行分辨率建模。机械论 RNA聚合酶转录和MutS启动DNA错配修复的研究将会扩大 更真实的生物学背景和对拥挤蜂窝环境的研究将继续 了解细胞环境对单分子动力学和功能的影响。最后， 将开发和实施从分子到细胞尺度的多尺度方法 在社区软件中。

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.