Building physical models for biomolecular organization and interactions

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，每个细胞都是一个生物物理“实验室”，生物物理建模为数据提供了一个概念框架。******本提案致力于建立生物分子组织和相互作用的物理模型，这些相互作用是细菌细胞中染色体组织和细菌膜渗透性的基础。它提供的一般物理图像可以对聚合物物理，软物质和生物医学应用（例如，肽抗生素的合理设计）的广泛主题产生影响。******众所周知，染色体的空间组织方式影响其生物学功能（例如，基因对蛋白质的可及性，如转录）。在这里，我们通过构建一个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：一个拥挤和有限空间中的异质环状聚合物。******染色体由其他分子修饰。在我们的模型中，链的非均匀性反映了它们在染色体上的不均匀分布。利用这个模型，我们将研究在拥挤和有限的空间中，链的异质性和链的组织是如何交织在一起的。该结果将有助于提供细菌染色体如何按照其生物学功能在空间上组织的定量图像，并有助于推进我们在聚合物物理和软物质方面的知识。******另一个有趣的物理建模来源是细菌膜的渗透性是通过它们与两亲分子，特别是膜活性抗菌肽（AMPs）的相互作用而改变的。已知阳离子amp选择性地附着并破裂细菌膜，细菌膜携带大量带负电荷的脂质。它们的工作方式为开发肽类抗生素提供了经验。******尽管在文献中普遍使用肽选择性作为“肽质量”的衡量标准，但肽选择性的概念尚未得到很好的理解，部分原因是我们缺乏定量模型。我们将开发一个肽选择性的物理模型，特别是一个显示选择性如何取决于细胞浓度的模型。该结果将有助于有效肽抗生素的设计。******与此相关的一点是革兰氏阴性菌（如大肠杆菌）被双层膜包围：“外”和“内”。外膜是不对称的，外层主要由聚阴离子脂多糖（LPS）分子组成。使用粗粒度模型，我们将研究LPS层或LPS膜如何受到阳离子amp的影响。结果将有助于阐明LPS在肽选择性中的作用。******我们的研究结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肽抗生素）

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).**