Doctor of Philosophy
Other advisers/committee members
Zhang, Xiaohui; Cheng, Xuanhong
The von Willebrand Factor (vWF) is a large multimeric protein in the blood that aids in blood clotting. It activates the clotting cascade at a specific time and a specific place, which is one of the human body's masterpieces in targeted molecular manipulation. Hydrodynamic or shear force triggers conformational changes of vWF, by which its potency and reactivity are regulated. In this thesis, we take inspiration from novel findings in the vWF experiments, and aim to describe the behaviors observed in this process within the context of polymer science. By understanding this physical principle, we hope to harness nature's ability to help us develop targeted drug therapy, which is capable to deliver drug wherever and whenever needed.After initial introduction of the blood clotting process, we first propose a novel bead- spring model in the presence of infinite medium. Contrary to the classic bead-spring model that each bead is connected by one type of spring, our model's beads are connected by finitely extensible nonlinear elastic (FENE) springs and Hookean springs consecutively. The motivation is that the A2 domain, which undergoes significant unfolding during single molecule stretching experiments, has been proven to be very flexible. Instead of modeling a monomer as one bead, more details inside each monomer and more complexity of vWF multimer has been captured by modeling vWF monomers as a highly flexible A2 domain with relatively very rigid domains on either side of A2. The A2 domain is modeled as a finitely extensible nonlinear elastic (FENE) spring capable of significant extension. At each end of the spring is a spherical bead to represent neighboring rigid domains. Adjacent monomers are connected by a tight harmonic spring1successively to form vWF multimers of desired length. In an effort to validate our mythology and generalize our results quantitatively, vWF multimers represented by this model have been probed to understand a single vWF multimer in both relaxation without flow scenarios and unfolding in response to shear flow circumstances.After investigating flow-induced changes in vWF multimer conformation, we extend our research further to study adhesion of vWF multimer by incorporating a collagen-coated surface to the vWF model in the second section of this thesis. During the blood clotting process, vWF undergoes a counterintuitive adsorption process and here we begin to develop the fundamental model required to understand this process. Because the presence of a pure surface will create a non-monotonic lift force, which greatly facilitate the desorption behavior of vWF multimer even under highly attractive surface, we add another A3 domain and collagen interactions representing by reversible ligand-receptor- type bonds based on bell model kinetics. The bonding and debonding rate between vWF multimers and collagen-coated surface is determined by the energy landscape i.e. binding and unbinding energy of bell model, which are measured by force spectroscopy and were extracted using the Dudko-Hummer-Szabo model under different temperature. The no- slip bond that the tensile force has no influence on the bond is being used firstly to counteract the lift force induced desorption. The results show that the adhesion process is still impeded by bead-wall hydrodynamic interactions, which is different from the experimental observations. The final section of this paper will be focused on the dynamics of vWF multimers in complex geometries, especially in a slit.
Ouyang, Wenli, "Characteristics of von Willebrand Factor multiuser in blood clotting" (2015). Theses and Dissertations. 1580.