Understanding the Roles of Molecular Interactions in Active Biological Processes

This dissertation presents our theoretical and computational studies on three biological processes: the stability of epigenetic memory in eukaryotic cells, the FtsZ-ring dynamics in bacterial cell division, and the cytoneme stabilization in Drosophila embryo. Although these processes are vastly different in their molecular contents, functions and biological contexts, their dynamics are all modulated by critical molecular interactions in the reaction system. Based on the existing knowledge about the biological processes, we developed our models, implemented the simulation to validate these models, and further applied our model to explain and predict behaviors of the system. Epigenetic memory is part of the inheritable information that organisms pass through generations. It is typically encoded as the modifications to nucleosomes that change the genes’ accessibility. It is known that epigenetic memory is closely related to trans-generational human diseases. In the first part of this thesis, we studied the stability of the epigenetic memory. We developed a reversible epigenetic modification reaction network, simulated its bistable dynamics and identified the key-driven factors that help to stabilize the epigenetic memory. We found that stable epigenetic memory requires active energy dissipation through the modification reaction steps. Our results suggested that there exists a minimum energy requirement for memory stabilization, which is set by the system's intrinsic tendency in erasing any encoded memory. Furthermore, we demonstrated that the coupling interaction between enzymes helps to amplify the effectiveness of the dissipated energy in elongating the encoded memory. Our results provided a novel insight into the bistable epigenetic memory phenomenon from the unique angle of energetics. The second part of this thesis centered around the dynamics of FtsZ-ring that drives the cell division. FtsZ protein is the prokaryotic homolog of tubulin that hydrolyzes GTP and assembles to filamentous structures. It is highly conserved across many species of bacteria. It has been recently discovered that the FtsZ-ring moves around the cell division site at a speed depending on its GTPase activity. To quantitatively understand this process, we incorporated the known biochemical and biophysical reactions into a rule-based modeling framework. We successfully reproduced the key FtsZ-ring assembling processes: the treadmilling dynamics, the recovering dynamics after photobleaching and the single molecule diffusive dynamics. Furthermore, we applied this model to investigate the molecular details of the FtsZ-ring treadmilling phenomenon. Our results indicated that the diffusion of FtsZ clusters in the FtsZ-ring is biased, which contributes to 70% of the total treadmilling velocity. We further demonstrated that the biased diffusion is originated from the structural Brown-Ratchet caused by molecular interactions within the FtsZ clusters. These findings provided deep insights into the dynamics of FtsZ-ring. Our model could further serve as a powerful tool for future studies in the field. The third system we studied is the Drosophila cytonemes. Cytonemes are protrusive structures extended from embryonic cells. They have been found to be essential for the long-range signal transduction. In this part of the thesis, we presented the modeling part of our collaborative studies on cytoneme stabilization. We developed a simplified subunit-based filamentous model to describe the growth, shrinkage, and translocation of protrusive structures from the cell surface and then simultaneously simulated the dynamics of multiple protrusions and established the quantitative relationship between the protrusion length and the homophilic trans-interaction strength. Our simulation results provided quantitative evidence supporting our hypothesis that the homophilic trans-interaction, mediated by the Ihog molecules, can lead to elongated stable cytonemes.

Author

• Yang, Chuxuan

Keyword

• Histone modification
• Cytoneme
• Rule-based model
• Monte Carlo simulation
• FtsZ ring

Date created

• 2019

Type of Work

• Thesis or Dissertation

License

• All rights reserved

Rights statement

• In Copyright

GW Unit

• Physics

Degree

Advisor

• Ganhui Lan, Assistant Professor of Physics, Dissertation Director

Committee Member(s)

• Xiangyun Qiu, Associate Professor of Physics, Committee Member
• Xiaoyan Zheng, Assistant Professor of Anatomy and Cell Biology, Committee Member

Persistent URL

•  https://scholarspace.library.gwu.edu/etd/44558d84h