NSF Award
2318053
Bacteriophages (phages), viruses that infect bacteria, have been the focus of attention in many scientific fields such as phage therapy, drug discovery, and nanotechnology, because phages are active regulators of bacterial microbiomes. Key steps in the phage growth process include: the packaging of the viral DNA inside a preformed icosahedral volume (called capsid), the three-dimensional arrangement of DNA inside the capsid and the delivery of the DNA molecule, from the capsid into the bacterial cell, at the time of infection. These three steps are all highly influenced by the biophysical properties of the DNA molecule in spatial confinement. In this project, the investigators will combine experiments and mathematical modeling to provide a thorough characterization of DNA organization inside phage capsids and its delivery at the time of infection. The research will bridge several mathematical disciplines including continuum mechanics (theory and simulations) of liquid crystals, analysis of free boundary problems, dynamics and knot theory. The interaction between the theoretical and experimental work is fashioned following the ideas of the Materials Genome Initiative, that fostered a systematic interconnected approach between mathematical modeling and experimental work, aimed at improving efficiency in the design and discovery of new materials. The project will train two graduate students and one postdoctoral fellow. <br/><br/>In this project, the investigators will focus on a paradigm shift in the field of DNA knotting due to spatial confinement by hypothesizing and rigorously proving, according to the theory by Landau and de Gennes, that DNA knots observed are line defects of a tensor field associated to liquid crystal configurations. This paradigm shift is aimed at better capturing the three-dimensional arrangement and topological properties of packaged DNA, the formation of DNA knots, and their dependence on the environmental ions. In parallel with the development of mathematical theory, new experimental work will be pursued. In particular, the research will explore the generation of knotted conformations exclusively driven by the liquid crystalline structure of confined DNA. The investigators will also develop models to study genome release from bacteriophages at the time of infection. The investigators will apply methods previously developed in the study of polyelectrolyte gels combined with tools from protein binding to develop a state-of-the-art approach to genome release. The mathematical problem consists of a constraint system of partial differential equations for an ionic two-phase media: water and DNA, that includes activation by ratchet forces. By combining modeling, analysis, and computation, the investigators aim at characterizing the time scales associated with the different mechanisms of genome delivery and simulate a full infection process for specific viruses.<br/><br/>This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.
