Building physical models for biomolecular organization and interactions

建立生物分子组织和相互作用的物理模型

• 批准号: RGPIN-2016-04224
• 负责人: Ha, BaeYeun
• 金额: $ 1.97万
• 依托单位: University of Waterloo
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2020
• 资助国家: 加拿大
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=709055
• 关键词: Building; physical; models; biomolecular; organization

The way biomolecular systems work has been an inspiring source for physics. Indeed, every cell is a biophysics "lab," and biophysical modelling offers a conceptual framework for data. This proposal is devoted to building physical models for biomolecular organization and interactions that underlie chromosome organization in a bacterial cell and bacterial-membrane permeability. The general physical pictures it offers can have an impact on a broad range of topics in polymer physics, soft matter, and biomedical applications (e.g., the rational design of peptide antibiotics). It is known that the way chromosomes are spatially organized influences their biological function (e.g., accessibility of genes to proteins as for transcription). Here, we seek a physical origin of this interdependence in a bacterial cell by constructing a polymer chromosome model: a heterogeneous ring polymer in a crowded and confined space. The chromosome is decorated with other molecules. The chain heterogeneity in our model is to reflect their uneven distribution along the chromosome. Using this model, we will examine how chain heterogeneity and chain organization are intertwined in a crowded and confined space. The outcome will be useful for offering a quantitative picture of how bacterial chromosomes are spatially organized as desired for their biological function and for advancing our knowledge in polymer physics and soft matter. Another intriguing source for physical modelling is the way bacterial membrane permeability is modified by their interactions with amphiphilic molecules, especially membrane-active antimicrobial peptides (AMPs). Cationic AMPs are known to selectively attach to and rupture bacterial membranes, which carry a large fraction of negatively-charged lipids. The way they work offers lessons for developing peptide antibiotics. Despite its popular use as a measure of "peptide quality" in the literature, the notion of peptide selectivity has not been well understood, partly because of our lack of a quantitative model. We will develop a physical model of peptide selectivity, especially one that shows how the selectivity depends on cell concentrations. The outcome will assist with the design of potent peptide antibiotics. A related point is that Gram-negative bacteria (e.g., E. coli) are enclosed by double membranes: "outer" and "inner." The outer membrane is asymmetrical with the outer layer mainly populated by polyanionic lipopolysaccharide (LPS) molecules. Using a coarse-grained model, we will study how the LPS layer or LPS membranes can be influenced by cationic AMPs. The outcome will help clarify the role of LPS in peptide selectivity. The outcomes of our studies will not only pave the way for understanding important cellular processes but also benefit other areas such as biomedical applications (e.g., peptide antibiotics for combating drug-resistant and/or Gram-negative bacteria).

生物分子系统的工作方式一直是物理学的灵感来源。事实上，每个细胞都是生物物理的“实验室”，生物物理模型为数据提供了一个概念性的框架。 这项建议致力于建立生物分子组织和相互作用的物理模型，这些组织和相互作用是细菌细胞中染色体组织和细菌膜通透性的基础。它提供的一般物理图片可以对聚合物物理、软物质和生物医学应用(例如，多肽抗生素的合理设计)的广泛主题产生影响。 众所周知，染色体在空间上的组织方式会影响它们的生物学功能(例如，基因对蛋白质的可及性，如转录)。在这里，我们通过构建聚合物染色体模型来寻找细菌细胞中这种相互依赖的物理起源：在拥挤和受限的空间中的异质环聚合物。 染色体上装饰着其他分子。我们模型中的链异质性是为了反映它们在染色体上的不均匀分布。使用这个模型，我们将研究在拥挤和受限的空间中，链异质性和链组织是如何交织在一起的。这一结果将有助于提供细菌染色体如何根据其生物学功能在空间上进行组织的定量图片，并有助于促进我们在聚合物物理和软物质方面的知识。 物理模拟的另一个有趣的来源是细菌的膜通透性是通过它们与两亲性分子，特别是膜活性抗菌肽(AMPs)的相互作用来改变的。众所周知，阳离子AMP选择性地附着和破坏细菌膜，细菌膜携带很大一部分带负电荷的脂类。它们的工作方式为开发多肽抗生素提供了经验教训。 尽管在文献中它被广泛用作“多肽质量”的衡量标准，但多肽选择性的概念还没有被很好地理解，部分原因是我们缺乏一个定量模型。我们将开发一个多肽选择性的物理模型，特别是一个显示选择性如何依赖于细胞浓度的模型。这一结果将有助于设计有效的多肽抗生素。 与此相关的一点是，革兰氏阴性菌(如大肠杆菌)被双层膜包裹：“外层”和“内层”。外膜是不对称的，外层主要是聚阴离子脂多糖(LPS)分子。使用粗粒模型，我们将研究阳离子AMP如何影响内毒素层或内毒素膜。这一结果将有助于阐明内毒素在多肽选择性中的作用。 我们的研究成果不仅将为理解重要的细胞过程铺平道路，而且还将有益于其他领域，如生物医学应用(例如，用于对抗耐药和/或革兰氏阴性细菌的多肽抗生素)。