Mechano-Biologically Informed Molecular Models of Flow Sensitive Biopolymers

在人体中，通过在血管损伤部位形成凝块来止血。 在与损伤相关的快速血流条件下，血浆蛋白血管性血友病因子（vWF）在粘附受损血管壁上的血小板和胶原蛋白方面起着不可或缺的作用，从而形成血小板栓。 vWF有效地感知血流，在高流量下将构象从紧凑的小球改变为细长形状;这揭示了血小板和胶原蛋白在vWF上的结合位点。 血管性血友病（vonWillebrand disease，vWF）是一种重要的心血管疾病，其发病率约占世界人口的1 ~ 2%，与血管性血友病（vonWillebrand disease，vWF）、血栓形成和动脉硬化密切相关。 虽然vWF的基本生物学特性已经阐明，但对vWF的详细生物力学特性以及这些特性如何决定其在不同流动环境中的结构和功能知之甚少。 这些信息不仅有助于更好地了解vWF，还可以为设计合成分子以寻求靶向药物治疗提供见解，推进联邦在健康和医学方面的利益。该项目将首次建立一个通用的实验和理论平台，以研究复杂的多域分子（如vWF）的力学性质。 先进的平台将为流动敏感生物聚合物在特定血管流动场景中的行为以及该行为如何取决于分子结构和生物表面化学提供变革性预测能力。 将实施单分子力谱，以系统地探测vWF单体片段、单体和多聚体的机械响应;由此获得的数据将用于优化新的粗粒分子模型，该模型以前所未有的定量准确度预测vWF机械行为。 该模型的预测能力将进一步提高通过荧光显微镜分析vWF在微流体流动室系统功能化的表面。 优化的模型将用于探索分子结构的变化如何影响不同流动条件下的生物功能。 这项工作将能够详细了解vWF构象变化的分子机制，并为生物启发材料设计和开发类似于已知生物聚合物功能的仿生设备奠定关键基础。 此外，这项研究将填补长期存在的关于vWF机械生物学的知识空白，并有可能为治疗血管性血友病提供新的治疗方法。 该项目将在生物分子研究的实验和理论方面教育本科生和研究生STEM学生，强调实验，计算和理论从业者之间多学科，多样化合作的必要性。 这种身临其境的STEM教育体验将为学生应对未来的技术挑战做好最好的准备。 通过相关的推广工作，这项工作将向技术和非技术社会受众展示高性能计算在探索复杂分子行为和推进人类健康和保健新解决方案方面的力量。

In human bodies, bleeding is stopped by forming a clot at the site of vascular damage. Under rapid blood flow conditions associated with injury, the plasma protein von Willebrand Factor (vWF) plays an indispensable role in sticking to both platelets and collagen on damaged vessel walls, allowing the formation of platelet plugs. vWF effectively senses blood flow, changing conformation in high flow from a compact globule to an elongated shape; this reveals binding sites on vWF for platelets and collagen. Abnormalities in vWF adhesion are involved in the pathogenesis of many cardiovascular diseases, such as von Willebrand disease (affecting 1 to 2% of world's population), thrombosis and arteriosclerosis. Although basic biological properties of vWF have been elucidated, little is known about the detailed biomechanical properties of vWF and how these properties dictate its structure and function in varying flow environments. Such information can abet not only better understanding of vWF; it can provide insight for the design of synthetic molecules in pursuit of targeted drug therapies, advancing federal interests in health and medicine.This project will establish, for the first time, a generalized experimental and theoretical platform to investigate the mechanical properties of complicated, multi-domain molecules such as vWF. The platform advanced will provide transformative predictive capability for how flow sensitive biopolymers behave in specific vascular flow scenarios and how that behavior depends on molecular architecture and biological surface chemistry. A single-molecule force spectroscopy will be implemented to systematically probe the mechanical response of vWF monomer fragments, monomers, and multimers; data so obtained will be used to optimize new coarse grain molecular models that predict vWF mechanical behavior with unprecedented quantitative accuracy. The model's predictive capabilities will be further enhanced via fluorescence microscopy analysis of vWF in microfluidic flow chambers with systematically functionalized surfaces. The optimized model will be used to explore how changes to molecular architecture influence biological functionality in varying flow conditions. This work will enable a detailed understanding of the molecular mechanisms underlying conformational changes of vWF and lay crucial groundwork toward biologically inspired materials design and the development of biomimetic devices that resemble the functionality of known biopolymers. In addition, the study will fill the long-standing knowledge gap on the mechanobiology of vWF, and potentially offer new therapeutic approaches to treat von Willebrand disease. This project will educate both undergraduate and graduate STEM students in experimental and theoretical aspects of biomolecular investigation, emphasizing the need for multi-disciplinary, diverse collaborations between practitioners of experiment, computation, and theory. Such immersive STEM educational experiences will best prepare students to confront technological challenges of the future. Through associated outreach efforts, this work will showcase for both technical and non-technical societal audiences the power of high performance computing in exploring complex molecular behavior and advancing new solutions in human health and wellness.