Molecular Simulations of the Cell

细胞的分子模拟

基本信息

批准号：
10220989
负责人：
ADRIAN Hamilton ELCOCK
金额：
$ 47.57万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-01 至 2023-07-31
项目状态：
已结题

项目摘要

Project Summary Experimental data from such fields as structural biology, proteomics, and genomics are providing enormous amounts of information about the intracellular world of bacteria. What is currently missing is a combined structural model of the bacterial cell that integrates these disparate sources of data in such a way that allows key biological processes to be simulated as they might occur in vivo. The goal of the proposed project, therefore, is to continue development of computational methods intended in the long-term to allow structural models of entire bacterial cells to be constructed and simulated. The laboratory has previously reported a structural model of the cytoplasm of the gram-negative bacterium Escherichia coli. Current and future work will seek to extend that work and focus on developing high-resolution models of the chromosome of E. coli and its nucleoid-associated proteins: current chromosome models are at levels of resolution too coarse to allow molecular-level interpretations of behavior. The resulting models will be used to explicitly simulate proteins searching for their genomic binding sites and to model aspects of short-time chromosomal dynamics that have recently become amenable to experimental study. In both cases it is anticipated that the ability to directly interpret the observed behavior in terms of the underlying chromosomal structure will provide important mechanistic insights unattainable by any other method. In addition to chromosomal work, efforts will continue to construct quantitatively-predictive models of the effects of crowded intracellular conditions on protein folding behavior. Accompanying these application-oriented studies will be method-development work focused on developing simple but realistic descriptions of interactions between all types of biomolecule that are found in the cell and on implementing methods to rapidly compute these and other interactions (e.g. hydrodynamics) on the cellular scale. Progress in each of these general project areas will be assessed by making repeated quantitative comparisons with experimental data that are already available in the literature for the exact same biomolecular systems. As well as potentially providing quantitative insights into a number of aspects of protein and chromosomal behavior in vivo, the proposed work will deliver to the community computer simulation code and accompanying potential functions suitable for modeling a wide range of biomolecular systems. The simulation code, the high-resolution models of the chromosome, and all other data accrued during pursuit of the proposed work, will be made freely available in downloadable form. The proposed work is relevant to public health because its long-term goal is the construction of a complete structural model of an important bacterial pathogen – Escherichia coli – and because it seeks to understand, through the use of molecular simulations, how the biological processes that underpin life operate in vivo. The former aspect of the work may lead to the identification of new therapeutic strategies for dealing with bacterial pathogens; the latter may illuminate intracellular disease states in higher organisms such as humans.

项目摘要来自结构生物学，蛋白质组学和基因组学等领域的实验数据正在提供巨大有关细菌细胞内世界的大量信息。目前缺少的是一个组合细菌细胞的结构模型，以使这些不同的数据来源整合到以下方式的方式关键的生物过程将在体内发生，以模拟它们。拟议项目的目标，因此，要继续开发长期打算的计算方法，以允许结构要构建和模拟的整个细菌细胞的模型。该实验室以前已经报道了革兰氏阴性细菌大肠杆菌的细胞质的结构模型。当前和未来的工作将寻求扩展这项工作，并专注于开发大肠杆菌染色体的高分辨率模型及其与核苷相关的蛋白质：当前的染色体模型的分辨率水平太粗允许对行为的分子级解释。结果模型将用于明确模拟搜索其基因组结合位点的蛋白质并建模短期染色体动力学的各个方面最近已经适合实验研究。在这两种情况下，都可以预期直接根据基础染色体结构来直接解释观察到的行为重要的机械洞察力是通过任何其他方法无法实现的。除了染色体工作，努力将继续构建拥挤细胞内条件影响的定量预测模型关于蛋白质折叠行为。伴随这些面向应用的研究将是方法开发侧重于开发所有类型的生物分子之间相互作用的简单但现实的描述在细胞和实施方法以快速计算这些相互作用的方法（例如，流体动力学）在细胞尺度上。这些一般项目领域的进展将由与文献中已经可用的实验数据进行重复的定量比较对于完全相同的生物分子系统。以及有可能为一个数字提供定量见解在体内蛋白质和染色体行为方面，拟议的工作将传递给社区计算机模拟代码和参与潜在功能，适合对广泛的范围进行建模生物分子系统。仿真代码，染色体的高分辨率模型和所有其他数据在追求拟议的工作期间应计，将以可下载的形式免费提供。拟议的工作与公共卫生有关，因为它的长期目标是建造完整的重要细菌病原体的结构模型 - 大肠杆菌 - 因为它试图理解，通过使用分子模拟，基础生命的生物过程如何在体内运行。这这项工作的以前方面可能会导致确定应对的新治疗策略细菌病原体；后者可能会照亮较高的生物体（例如人类）中的细胞内疾病。