Charge matters: Pursuing the most common, and least understood molecular interactions in cells PROJECT SUMMARY / ABSTRACT The long-term objective of the Sel lab is to determine and understand how ion fluxes and electrostatic interactions regulate fundamental biological processes that promote stress tolerance in bacteria. The central problem to be addressed: The vast majority of molecular interactions that occur within any living cell have remained obscure. How can this be? Nearly all molecular interactions that have been studied to date, and on which our current understanding of biology is based on, are covalent interactions. These interactions are strong, making them suitable for experimental measurements. However, the vast majority of interactions among molecules within the cell are non-covalent interactions that are based on electrostatics. Electrostatic interactions can be weak and short-lived, and thus their measurements pose a great technical challenge. Consequently, how such interactions are regulated and what functions they play in cells remains largely unknown. To bridge this gap, we propose a research program to develop new devices, techniques, and a theoretical framework to investigate the functional roles of electrostatic interactions, specifically in bacterial cells and biofilm communities. Impact: The proposed work aims to investigate the regulation of ionic interactions and their functional roles in bacteria, to better understand and control their tolerance to antibiotics. The resulting findings will determine how changes in ionic strength and composition affect cell physiology. We will thus begin to characterize the dynamics of the prokaryotic ?metallome?. We will also integrate quantitative experiments with physics-based theoretical approaches to identify general principles governing electrostatic interactions that can be applied beyond our bacterial model systems. Given the tremendous number of ionic interactions within any given cell, it is very likely that our work will uncover a new layer of molecular regulation of fundamental biological processes. Specifically, we postulate the hypothesis of ?ionic allostery?, where we propose that cells regulate their cytoplasmic ion composition to modulate electrostatic interactions, and thereby globally regulate transcription and translation. In particular, ionic interactions may play a crucial role in bacterial cell fate decisions, such as entry into, and exit from dormancy, which is the major cause of antibiotic resistance. Our work will thus reveal whether ?the central dogma of biology? is modulated by changes in the ionic composition and strength of the cytoplasm and provide a new paradigm for understanding and controlling the regulation of fundamental stress responses in bacteria.

Public Health Relevance

The proposed research will investigate the functional roles of electrostatic interactions in the regulation of transcription and translation in bacteria and their biofilm communities, which due to their notorious tolerance to antibiotics pose a critical public health threat. In particular, we aim to establish a new paradigm for understanding how electrostatic interactions in bacteria can regulate cell fate decisions, such as the entry into, and exit from dormancy, which is the major cause of bacterial tolerance to antibiotics.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Unknown (R35)
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Special Emphasis Panel (ZRG1)
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Brazhnik, Paul
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University of California, San Diego
Schools of Arts and Sciences
La Jolla
United States
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