Molecular Simulations of the Cell

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提供了大量的 关于细菌细胞内世界的大量信息。目前缺少的是一个综合的 细菌细胞的结构模型，它以这样一种方式整合了这些不同的数据来源， 关键的生物过程，因为它们可能发生在体内模拟。拟议项目的目标， 因此，是继续发展计算方法，以便在长期内允许结构 构建和模拟整个细菌细胞的模型。该实验室此前曾报道， 革兰氏阴性细菌大肠杆菌细胞质的结构模型。目前和今后工作 将寻求扩展这项工作，并专注于开发E.杆菌 及其核相关蛋白：目前的染色体模型的分辨率水平太粗糙， 允许分子水平的行为解释。生成的模型将用于显式模拟 蛋白质寻找其基因组结合位点，并模拟短期染色体动力学方面 最近已经可以进行实验研究。在这两种情况下，预计 根据潜在的染色体结构直接解释观察到的行为将提供 任何其他方法都无法获得的重要的机械见解。除了染色体工作， 将继续构建拥挤细胞内条件影响的定量预测模型 蛋白质折叠行为。伴随着这些面向应用的研究将是方法开发 工作重点是开发简单但现实的描述所有类型的生物分子之间的相互作用 在细胞中发现的，以及实现快速计算这些和其他相互作用的方法（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以下方面评估： 与文献中已有的实验数据进行反复的定量比较 完全相同的生物分子系统。以及潜在地提供一些定量的见解， 蛋白质和染色体在体内的行为方面，拟议的工作将交付给社会 计算机模拟代码和伴随的势函数，适用于模拟各种 生物分子系统模拟代码，染色体的高分辨率模型，以及所有其他数据 将以可下载的形式免费提供。 拟议的工作与公共卫生有关，因为其长期目标是建立一个完整的 一个重要的细菌病原体-大肠杆菌-的结构模型，因为它试图了解， 通过分子模拟的使用，支持生命的生物过程如何在体内运作。的 这项工作的前一方面可能会导致确定新的治疗策略， 细菌病原体;后者可以阐明高等生物体如人类的细胞内疾病状态。

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.