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

生物功能来自组成细胞、组织和生物体的分子。在高浓度下，相互作用的生物分子通常形成决定生物功能的中间或介观结构，但这些结构的性质不能通过单独测量分子的生化性质来确定。由具有扰动相互作用的生物分子以及病毒和细菌的作用形成的介观结构与影响全球数百万人的一系列病理有关，包括神经退行性疾病、癌症、血液疾病、流感等传染病和细菌感染。软物质物理学是解决这一生物挑战的一种很有前途的方法，其目的是为介观和宏观尺度上的性质和过程如何从分子组成中产生提供一致的物理描述。然而，这需要建立在精确的生物分子相互作用基础上的物理模型，以及能够模拟跨长度尺度的生物物理过程的工具。在这个项目中，我将建立一个理论框架来预测宏观生物功能如何从相互作用的微观生物分子形成的介观结构的性质中显现出来。我将在三个实验上易于处理和临床相关的生物系统的背景下建立、验证和应用该框架，这些系统具有强大的潜在物理联系-我已经确定了一个国际合作者网络来执行验证实验。我将实现以下目标：1)将蛋白质的分子相互作用与生物分子凝聚体的介观性质及其对细胞宏观功能的影响联系起来。最近生物学范式的转变揭示了许多人类蛋白质和RNA可以在细胞条件下凝聚或聚集形成液体、凝胶或固体结构。生物分子缩合物是这一过程的一个生理例子，已被认为与神经退行性疾病、传染病和癌症等疾病有关。2)将噬菌体的分子相互作用与噬菌体液滴的介观性质及其对细菌生物膜宏观功能的影响联系起来。细菌生物膜是抗菌素耐药性的主要原因，据认为，抗菌素耐药性每年导致全球70万人死亡，如果不采取行动，到2050年，累计成本将达到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有重要影响，但为了帮助改善与此类细菌感染相关的许多疾病的治疗，我们需要了解使表达噬菌体的细菌具有这些好处的机制。3)将血红蛋白纤维的分子相互作用与纤维聚集体的介观性质及其对镰状细胞血液宏观功能的影响联系起来。红细胞的病理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，血液粘度增加，在缺氧条件下可能会堵塞，如果不治疗会导致死亡。目前正在努力开发SCD的遗传和药物治疗方法，但我们缺乏工具来确定特定治疗策略的优先顺序，或者在患者从生理上表现出来之前对患者进行临床监测和识别并发症。每个生物系统中的具体结果将与影响全球数百万人的分子疾病和细菌感染相关，总体框架将适用于更多的生物系统和广泛的疾病。

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.