Master of Science
The von Willebrand Factor (vWF) is a large multimeric protein in the blood that aids in blood clotting. It activates the clotting cascade at specific time and specific place, which is one of the human body’s masterpieces in targeted molecular manipulation. Hydrodynamic forces trigger conformational changes of vWF, by which its potency and reactivity are regulated. In this thesis, inspiration is taken from novel findings in vWF experiments. The present study aims to describe the behaviors in this process within the context of polymer science. Understanding the basic physical principle helps us to develop targeted drug therapy, which is capable to deliver drug wherever and whenever needed.After the introduction of blood clotting process, researchers in our group propose a novel bead-spring model. Contrary to classic bead-spring model that each bead is connected by one type of spring, the new model’s beads are connected by finitely extensible nonlinear elastic (FENE) springs and Hookean springs consecutively. The motivation is that the A2 domain, which will undergo significant unfolding process during 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 have 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, which is capable of significant extension. At each end of the spring is a spherical bead, which is used to represent neighboring rigid domains. In addition, the adjacent monomers are connected by a tight harmonic spring successively to form the vWF multimers of desired length. In an effort to validate our mythology and generalize our results quantitatively, it is necessary to study the vWF multimers represented by this noval model in both relaxation without flow scenarios and unfolding in response to specific flow circumstances.Since other researchers in our group have already studied the behaviors of a single vWF multimer unfolding in response to shear flow, here we extend our research further to the behaviors in response to extensional flow. The first and second chapter of this thesis state a brief introduction of blood clotting process and the simulation methodology which uses the noval model proposed by researchers in our group. The third chapter includes all the relevant calculation, analysis, results and discussion in details. Finally, the last chapter presents a comprehensive summary of the behaviors of vWF unfolding process in respond to extensional flow. From the research, it concludes that flow intensity and molecular size do have profound influences on the behavior characteristics of vWF multimer unfolding process. A certain length chain has been proven to unfold much faster in response to stronger extensional flow. Moreover, longer vWF chains have been proven to have more potential to unfold. Thus, comparing with shear flow, vWF multimers will unfold faster and stronger in response to extensional flow.
RONG, XINTONG, "Conformational changes of von Willebrand Factor multimer subject to extensional flows" (2015). Theses and Dissertations. 2784.