Building physical models for biomolecular organization and interactions

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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).