Colloidal physics modeling of biomolecular behavior to enable cell building
Abstract/Contents
- Abstract
- Building cells from scratch requires understanding how molecules -- the building blocks of cells -- move and interact to produce behavior. To better address this challenge I apply colloidal physics -- how microscopic particles behave in liquids -- to cell biology, leveraging protein synthesis as a model process. Specifically, I develop a modeling framework for representing the physical motion and chemical reactions of individual molecules in the full context of crowded cytoplasm, showing how individual tRNA and ribosomes diffuse and interact to enable protein synthesis. Using my framework, I elucidate a putative mechanism underlying how ribosomes become more productive in faster growing cells, an experimental observation that has remained unexplained for 50 years. Specifically, I show that the nucleoid-excluded cytoplasm, where translation primarily occurs, becomes three times more packed with molecules in faster growing cells. While increased packing slows molecular movement down, molecules also become closer together, a general phenomenon that enables matching tRNA and ribosomes to find each other more quickly and thus speeds up protein synthesis. I then explore the expected properties of cytoplasm for hypothetical cells that grow faster than ever observed. I predict that further increases in crowding would provide diminishing returns for or hinder protein synthesis, suggesting a physical limit on growth rate. Finally, I extend colloidal physics modeling directly to the design of synthetic cells by calculating how the relative abundances of tRNA can be engineered to provide optimal protein synthesis strategies for both wild-type and codon-reduced genomes. Engineered tRNA abundances are predicted to enable up to ~20% faster and ~50% slower protein synthesis compared to natural abundances. Colloidal physics modeling and engineering can be expanded across cell types and processes, supporting the general design and construction of cells.
Description
| Type of resource | text |
|---|---|
| Form | electronic resource; remote; computer; online resource |
| Extent | 1 online resource. |
| Place | California |
| Place | [Stanford, California] |
| Publisher | [Stanford University] |
| Copyright date | 2021; ©2021 |
| Publication date | 2021; 2021 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Author | Maheshwari, Akshay J |
|---|---|
| Degree supervisor | Endy, Andrew D |
| Thesis advisor | Endy, Andrew D |
| Thesis advisor | Covert, Markus |
| Thesis advisor | Zia, Roseanna |
| Degree committee member | Covert, Markus |
| Degree committee member | Zia, Roseanna |
| Associated with | Stanford University, Department of Bioengineering |
Subjects
| Genre | Theses |
|---|---|
| Genre | Text |
Bibliographic information
| Statement of responsibility | Akshay Maheshwari. |
|---|---|
| Note | Submitted to the Department of Bioengineering. |
| Thesis | Thesis Ph.D. Stanford University 2021. |
| Location | https://purl.stanford.edu/tt947kz0351 |
Access conditions
- Copyright
- © 2021 by Akshay J Maheshwari
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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