Charge matters: Pursuing the most common, and least understood molecular interactions in cells

电荷很重要：追求细胞中最常见、最不为人理解的分子相互作用

• 批准号: 10308671
• 负责人: Gurol Mehmet Suel
• 金额: $ 55.3万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-01 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10308671
• 关键词: Address; Affect; Antibiotic Resistance; Bacteria; Bacterial Model; Binding; Biological Models; Biological Process; Biology; Cell physiology; Cells; Charge; Communities; Covalent Interaction; Cytoplasm; Devices; Electrostatics; Genetic Transcription; Ionic Strengths; Ions; Measurement; Microbial Biofilms; Molecular; Physics; Play; Public Health; Regulation; Research; Role; Techniques; Transcriptional Regulation; Translations; Work; antibiotic tolerance; base; biological adaptation to stress; experimental study; programs; stress tolerance

Charge matters: Pursuing the most common, and least understood molecular interactions in cells PROJECT SUMMARY / ABSTRACT The long-term objective of the Süel 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.

收费问题：追求最常见，最不了解的 细胞中的分子相互作用 项目总结/摘要 Süel实验室的长期目标是确定和了解离子通量和静电是如何 相互作用调节基本的生物过程，促进细菌的胁迫耐受性。 需要解决的中心问题：任何生物体内发生的绝大多数分子相互作用 细胞仍然是模糊的。怎么会这样？几乎所有的分子间相互作用都被研究过， 我们现在对生物学的理解是基于共价相互作用。这些相互作用 这使得它们非常适合实验测量。然而，绝大多数人之间的互动 细胞内的分子是基于静电的非共价相互作用。静电相互作用 可能是微弱和短暂的，因此它们的测量构成了巨大的技术挑战。因此如何 这种相互作用是受调节的，它们在细胞中发挥什么功能在很大程度上仍然是未知的。以弥补这一 间隙，我们提出了一个研究计划，以开发新的设备，技术和理论框架， 研究静电相互作用的功能作用，特别是在细菌细胞和生物膜社区。 影响：拟议的工作旨在研究离子相互作用的调节及其在 细菌，以更好地了解和控制他们对抗生素的耐受性。结果将决定如何 离子强度和组成的变化影响细胞生理学。因此，我们将开始描述动力学特征 原核生物的“金属体”我们还将把定量实验与基于物理的理论相结合。 方法，以确定一般原则，管理静电相互作用，可以适用于超越我们的 细菌模型系统。考虑到在任何给定的细胞内离子相互作用的巨大数量， 我们的工作将揭示基本生物过程的分子调控的新层面。具体地说， 我们提出“离子变构”假说，即细胞调节其胞质离子 在一些实施方案中，本发明的组合物用于调节静电相互作用，从而全局调节转录和翻译。在 特别地，离子相互作用可能在细菌细胞命运决定中起关键作用，例如进入和离开。 休眠是抗生素耐药性的主要原因。因此，我们的工作将揭示“中央 生物学教条”是由细胞质的离子组成和强度的变化来调节的， 了解和控制细菌基本应激反应调节的新范式。