Final Model ProjectFibrinPHYS 053-001April 27, 2010Jake StringfieldPatrick MosebyMichael BebenCalvin Lewis Jr.Part A:Clot Formation in Human Blood This project is focused on describing and modeling the overall process of hemostasis inhumans, with a particular focus on the role that the protein fibrinogen plays in the formation ofthrombi. Understanding this process is important for multiple reasons. This is a process thatoccurs in a similar way in almost every mammal, so it is clear that this is a very essential processfor life: without clotting, blood would escape through holes worn in vessel walls, and oxygenwould not be delivered to the body, leading to death. While the process of coagulation is wellconserved in most mammals, the specifics of the human clotting are of most scientific interest,because of the medical applications that a better knowledge of clotting could advance. It isimportant that all processes involved in clot formation are functioning properly; a mutation thatinactivates a single clotting factor can lead to hemophilia, while overactive clotting mechanismscan lead to heart attack, stroke, or other embolism. Besides the important medical significancethat this process has, an understanding of the mechanisms of clotting will be valuable to purescience, with relevance to nanotechnology, biology, and the physics of protein mechanics.The blood is a very complex solution of ions, chemical messengers, cells, and proteins.Blood carries oxygen, nutrients, and water to every cell in your body, sustaining theirmetabolism, and keeping them alive. It helps to fight off infections, keeping the body healthy. Itremoves waste and toxins from cells and safely disposing of them. All of these crucial functionsdepend on blood being delivered, and this is why hemostasis is so important. The proteinsresponsible for clotting, collectively referred to as clotting factors, are in constant circulation inthe blood, along with many other substances. However, all of these proteins are inactive innormal blood. Certain proteins, called subendothelial proteins, contained behind theendothelium, the one-cell-thick wall of blood vessels, enter the blood stream through an injuryto the endothelium. The other key component in blood clot formation are the platelets, cellfragments to which, along with their role in clotting, produce growth factors, that speed healingin regions where the blood vessels are damaged. All of these components work together in a complex way to form clots. Whenendothelial cells are ruptured, subendothelial proteins are exposed to the blood stream. Theseproteins, including tissue factor and von Willebrand Factor, begin a cascade of conformationalchanges in the clotting factors present in the blood stream, as well as activating nearbyplatelets. The newly activated platelets, which begin as roughly spherical cell fragments, willalso change shape, growing protrusions that help facilitate their binding to each other, to thearea of the clot, and to clotting factors. Platelets then make up the primary hemostasis, a plugformed from activated platelets at the site of the rupture, held together by various clottingfactors. At this point the secondary hemostasis, consisting mainly of clotting factor 1, fibrinogen,will begin to form. The cascade of clotting factors will at this point lead to a surge of thrombin,which activates the fibrinogen. Fibrinogen will then bind to itself, forming fibrin, a network ofstrong and stretchy fiber that will seal the clot securely.As with all proteins, the structure of fibrinogen is key to its function. Fibrinogen is afibrillar protein that polymerizes, as described above, to form a viscoelastic gel. Activation offibrin severs the ends of the BβN domain, exposing sticky knobs that can bind to adjacentfibrinogen molecules at their holes in their D region. This results in a strong staggered formationof fibrinogen molecules within the fiber they make up, and the lack of rigidity in the BβNdomain is likely one of the ways that fibrin stretches. The αC domain also plays a role in bindingand stretching, but it is less understood. The coiled coil domain that makes up most of thelength of the protein is also believed to be involved in stretching. All together, the structure ofthe protein can, in some cases, allow stretching by a factor of six before breaking, making fibrinthe most flexible biological polymers yet. Proteins stretch when strain uncoils them from their preferred, most stable state. Shownabove is the crystalline structure of fibrinogen, but under stress certain interactions would bebroken in order to accommodate the forces applied to the molecule. One of the maininteractions that will be broken is hydrogen bonds. These bonds are based upon magneticinteractions between the hydrogen atoms bonded to nitrogen atoms, and oxygen atoms.Because of the high electronegativity of both nitrogen and oxygen, the hydrogen atoms willhave most of their electron cloud stolen from them, giving them a slight positive charge.Likewise the oxygen atoms will have slightly more electron density, and will have a slightnegative charge. The interactions between these atoms are analogous to natural magnets,because they can be pulled apart and reformed if stress is applied and released. As the proteinis stretched, hydrogen bonds will break until eventually only the carbon-carbon-nitrogenbackbone resists, at which point it will take far more force to stretch the molecule any further. Inthis way force will be distributed to adjacent fibrinogen molecules in the clot, allowing the fibrinto have enough strength and flexibility to function in the highly dynamic environment of pulsingblood.Part B:Model #1What We Are ModelingOur first model was of a blood clot, formed in a small vessel. We sought to represent the function of fibrin and platelets in the process of forming a clot. Our model clot is different from regular clots in that usually the clot forms on a small area of the vessel where a tear has occurred. Our model shows a vessel that is completely occluded.(This is when a thrombus occurs; if that thrombus breaks free, it forms an embolus.) Materials and ReasonsWe built the “vessel wall” by making a geometrically