Modelling self-assembly and dynamics of biophysical & soft matter systems

本申请中提出的研究重点是控制“生物物质”和“生物材料”的物理和物理过程。目标是了解生命物质的基本物理过程，并将这些知识应用于基于聚合物、胶体和表面活性剂组装的新型功能软材料的设计。“生物物质”一词是指存在于生物物质中的分子、材料和结构，例如，脂质、蛋白质、膜和DNA，在它们的自然环境中。另一方面，“生物材料”是指使用有机/生物分子或结构作为构建块或其操作原理的人造或设计材料。我提出的计划有两个主要主题：1)细胞分裂和迁移的理论和计算建模；2)淀粉样蛋白聚集的自组装的多尺度建模。这两个主题都集中在复杂生物和软物质的自组装和组织的物理学上。正如将要描述的，这两个主题共享几个方法上的联系，从概念上讲，它们涉及不同层次的膜界面的物理细节。这两个主题的专业知识都是基于我以前在建模生物和软物质系统方面的研究。在细胞分裂中，机械特性和生物化学调节之间的相互作用是细胞分裂的核心，但人们对其了解甚少。机械性质的基本重要性是显而易见的：所有的细胞，真核和原核细胞，都有一个细胞骨架。细胞骨架是由一种叫做肌动蛋白的蛋白质组成的纤维网络，它位于细胞内部的细胞膜上。在细胞分裂和细胞运动的过程中，这个网络必须以一种可控的方式改变其性质——甚至局部解体，然后重新组装。另一方面，在淀粉样蛋白聚集过程中，膜内错误折叠的蛋白质自组装，形成孔并杀死细胞。我们研究了控制自聚集的微观物理机制。从长远来看，这些知识对于开辟新的治疗途径至关重要。我们使用的方法是大规模计算多尺度建模和分析理论。与实验的直接比较将与已建立的合作者进行。上述问题定义了一个巨大的挑战：1)发现驱动和控制自组装的物理原理对于理解生物过程至关重要，例如蛋白质-蛋白质相互作用和淀粉样蛋白疾病中特有的有毒寡聚物组装的形成。这些知识是药物和合成生物实体（如人造细胞）自下而上设计的基础。2)了解物理相互作用的性质和强度以及软物质和生物物质的集体特性对于设计可以由外部刺激（如机械力或激光照明）控制的人造材料至关重要。应用包括超灵敏的分子传感器、药物对接和设计新的功能材料。除了新的基础知识之外，这项研究还将导致方法和软件开发（开源），从而使科学界受益。我的团队在为生物物理和软物质系统提供新的模拟软件和参数方面有着非常强大的记录。预计这一结果将引发其他团体的实验和应用研究，并有望导致消费者应用。这样的发展将为当地和加拿大的工业研发带来额外的好处。

The research proposed in this application focuses on the physics and physical processes controlling 'biological matter' and 'biomaterials'. The goals are to understand the fundamental physical processes in living matter and to apply that knowledge to the design of new functional soft materials based on polymers, colloids and surfactant assemblies. The term 'biological matter' refers to molecules, materials and structures present in living matter, for example, lipids, proteins, membranes, and DNA, in their natural environment. 'Biomaterials', on the other hand, refers to man-made or designed materials that use organic/biological molecules or structures as building blocks, or for their principles of operation. The program I am proposing has two main themes: 1) Theoretical and computational modelling of cell division and migration and 2) multiscale modelling of the self-assembly of amyloid aggregation. Both themes focus on the physics of self-assembly and organization in complex biological and soft matter. As will be described, these two themes share several methodological connections and conceptually, they involve the physics of membrane interfaces at different levels of detail. Expertise in both themes is based on my previous research in modelling biological and soft matter systems. In cell division, the interactions between mechanical properties and biochemical regulation that are at the heart of cell division remain poorly understood. The fundamental importance of mechanical properties is easy to see: All cells, eukaryotic and prokaryotic, have a cytoskeleton. The cytoskeleton is a filament network consisting of a protein called actin as its main component, and is located on the cell membrane inside the cell. During cell division and cell motion, this network must change its properties – or even disintegrate locally and then re-assemble – in a controlled manner. In amyloid aggregation, on the other hand, membrane embedded misfolded proteins self-assemble, form pores and kill cells. We investigate the microscopic physical mechanisms that control self-aggregation. In the long term, such knowledge is crucial for opening new avenues of treatment. The methods we use are large-scale computational multi-scale modelling and analytical theory. Direct comparisons to experiments will be done with established collaborators. The problems described above define a Grand Challenge: 1) Finding the physical principles that drive and control self-assembly are crucial for understanding biological processes such as protein-protein interactions and formation of the toxic oligomeric assemblies that are characteristic in amyloid diseases. This knowledge is fundamental for bottom-up design of drugs and synthetic biological entities such as artificial cells. 2) Knowledge of the character and strength of the physical interactions together with collective properties in soft and biological matter is crucial for designing man-made materials that can be controlled by external stimuli such as mechanical forces or illumination by laser light. Applications include ultra-sensitive sensors for molecules, drug docking and designing new functional materials. In addition to new fundamental knowledge, this research will lead to method and software development (open source), benefiting the scientific community. My group has a very strong track record of contributing to and providing new simulation software and parameters for biophysical and soft matter systems. It is also anticipated that the results will spark experimental and applied research by other groups, and hopefully lead to consumer applications. Such developments would lead to added benefits for local and Canadian industrial R&D.