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.
