Multiscale modelling and control of soft biological matter: Linking biomolecular interactions to macroscopic function

软生物物质的多尺度建模和控制：将生物分子相互作用与宏观功能联系起来

• 批准号: MR/V022385/1
• 负责人: Philip Pearce
• 金额: $ 184.48万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FV022385%2F1
• 关键词: Multiscale; modelling; control; soft; biological

Biological functions emerge from the molecules that make up cells, tissues and organisms. At high concentration, interacting biomolecules often form intermediate or mesoscopic structures that determine biological function, but the properties of these structures cannot be identified through measurements of the biochemical properties of the molecules in isolation. Mesoscopic structures formed by biomolecules with perturbed interactions, and by the actions of viruses and bacteria, have been implicated in a range of pathologies that affect millions of people worldwide, including neurodegenerative diseases, cancer, diseases of the blood, infectious diseases such as influenza, and bacterial infections. Soft matter physics, in which the aim is to provide a consistent physical description of how properties and processes at mesoscopic and macroscopic length scales emerge from molecular constituents, is a promising approach to address this biological challenge. However, this requires physical models grounded in accurate biomolecular interactions, and tools that can simulate biophysical processes across length scales.In this project, I will build a theoretical framework to predict how macroscopic biological functions emerge from the properties of mesoscopic structures formed by interacting microscopic biomolecules. I will build, validate and apply the framework in the contexts of three experimentally tractable and clinically relevant biological systems with strong underlying physical links - I have identified an international network of collaborators to perform the experiments for validation. I will achieve the following objectives:1) To connect the molecular interactions of proteins to the mesoscopic properties of biomolecular condensates and their effects on macroscopic functions in cells.A recent paradigm shift in biology has revealed that many human proteins and RNA can condense or aggregate to form liquid-, gel- or solid-like structures under cellular conditions. Biomolecular condensates, a physiological example of this process, have been implicated in diseases including neurodegenerative diseases, infectious diseases and cancer. However, it is largely unknown how physiological and pathological molecular interactions contribute to condensate functions in health and disease.2) To connect the molecular interactions of phages to the mesoscopic properties of phage droplets and their effects on macroscopic functions in bacterial biofilms.Bacterial biofilms are a leading cause of antimicrobial resistance, which is thought to cause 700,000 deaths each year globally, with a cumulative cost of $100 trillion by 2050 if no action is taken. Recent evidence suggests that viral phages expressed by various bacteria may have important effects on antibiotic resistance, but to contribute to improved treatments for the many diseases associated with such bacterial infections, we need to understand the mechanisms that confer phage-expressing bacteria with these benefits.3) To connect the molecular interactions of hemoglobin fibrils to the mesoscopic properties of fibril aggregates and their effects on macroscopic functions in sickle cell blood.Pathological biophysical dynamics of red blood cells are a hallmark of diseases of the blood that affect millions of people worldwide, including sickle cell disease (SCD). In SCD, blood increases in viscosity and may clog in deoxygenated conditions, causing death if left untreated. There is an ongoing clinical effort to develop genetic and pharmacological treatments for SCD, but we lack tools to prioritise specific treatment strategies or to clinically monitor patients and identify complications before they manifest physiologically.The specific outcomes in each biological system will have relevance to molecular diseases and bacterial infections that affect millions of people worldwide, and the general framework will be applicable to further biological systems and a vast array of diseases.

生物学功能来自组成细胞，组织和生物的分子。在高浓度下，相互作用的生物分子通常形成确定生物学功能的中间或介观结构，但是这些结构的性能无法通过分离中分子的生化特性的测量来鉴定。由具有扰动相互作用的生物分子形成的介质结构以及病毒和细菌的作用已与一系列影响全球数百万人的病理，包括神经退行性疾病，癌症，血液，感染性疾病，例如流感型流感和细菌性疾病。软物质物理学的目的是提供一致的物理描述，以了解从分子成分中出现介观和宏观长度尺度的性质和过程，是解决这一生物学挑战的一种有希望的方法。但是，这需要以准确的生物分子相互作用为基础的物理模型，以及可以在长度尺度上模拟生物物理过程的工具。在该项目中，我将建立一个理论框架，以预测宏观生物学功能如何从通过相互作用的微观生物细菌形成的中学结构的性质中出现。我将在三个具有实验性处理且与临床相关的生物系统的背景下建立，验证和应用该框架具有牢固的基础物理联系 - 我已经确定了一个国际合作者网络来执行实验以进行验证。我将实现以下目标：1）将蛋白质的分子相互作用连接到生物分子冷凝物的介观特性及其对细胞中宏观功能的影响。生物学的最新范式变化已经表明，许多人类蛋白质和RNA可以凝聚或聚集以形成液体 - 固体固体或固体型结构下的液体型结构。生物分子冷凝物是该过程的生理例子，与包括神经退行性疾病，传染病和癌症在内的疾病有关。然而，在很大程度上未知生理和病理分子相互作用如何促进健康和疾病中的凝结功能。2）将噬菌体的分子相互作用与噬菌体滴剂的介质特性联系起来，对每个引起抗菌病的导致抗菌症状的导致抗菌症状的宏观功能及其对宏观函数的影响。在全球范围内，如果没有采取任何措施，到2050年累计成本为100万亿美元。最近的证据表明，各种细菌表达的病毒噬菌体可能对抗生素耐药性具有重要作用，但要改善与此类细菌感染相关的许多疾病的治疗，我们需要了解与这些益处相关的噬菌体对这些好处的表达噬菌体的机制。镰状细胞血液中的宏观功能。红细胞的人行为生物物理动力学是影响全球数百万人的血液疾病的标志，包括镰状细胞病（SCD）。在SCD中，血液的粘度增加，可能在脱氧条件下堵塞，如果未治疗，会导致死亡。正在进行的临床努力来开发SCD的遗传和药理治疗方法，但是我们缺乏优先级的特定治疗策略或在临床上监测患者并在生理上表现出并发症的工具。每个生物系统中的特定结果将与分子疾病和细菌感染相关，并影响全球范围内的人群和一般范围的一般性范围和适用于全球范围的几个人。

项目成果

Universal dynamics of biological pattern formation in spatio-temporal morphogen variations

时空形态发生素变化中生物模式形成的普遍动力学

• DOI: 10.1101/2022.03.18.484904
• 发表时间: 2022
• 作者: Dalwadi M

Biophysical basis of phage liquid crystalline droplet-mediated antibiotic tolerance in pathogenic bacteria

噬菌体液晶液滴介导的病原菌抗生素耐受的生物物理基础

• DOI: 10.1101/2022.12.13.520211
• 发表时间: 2022
• 作者: Böhning J