of the molecular interactions and mechanisms of human tissue factor (TF) is critical to our understanding of the basis of cell function in vascular disease, inflammation, and cancer. Effective modulation of these molecular mechanisms has yet to be achieved by therapeutic agents. The goal of the Computational Modeling Project within the Program is to aid in the construction and evaluation of models of interactions of TF, both in its role of extracellular initiation of blood coagulation, and its intracellular signaling functions, which appear to have a role in angiogenesis. The computational work will be based upon structural data and mutagenic experiments, and will encompass homology modeling, molecular mechanisms and dynamics, protein-substrate and protein-protein docking. This work will be done in close collaboration with Dr. Wolfram Ruf in Project 2 and Dr. Tom Edgington in Project 3. Combining structural information on the individual molecular components we can use computational docking to propose models of molecular interaction that can then be tested and verified with biochemical and mutational experiments. The experimental results can then be fed back to our modeling procedures to refine and constrain the models. This feedback between experiment and computation provides a strong methodology for developing realistic structural descriptions of these important interactions. The following specific aims will be carried out:
in Aim 1 we will enhance and integrate the various tools for docking, refinement, visualization, and quantification within a component-based environment that facilitates interoperability and extensibility;
in Aim 2 we will build and refine a model of the ternary complex between human tissue factor, factor VIIa and factor Xa;
in Aim 3 we will build a model of the interaction of the TF pathway inhibitor (TFPI-1) docking to the ternary complex. This model will provide a picture of an important regulatory interaction, and will also provide validation of the ternary complex model;
in Aim 4 we will develop models of the substrate interactions with TF. VIIa. Based upon the Xa structure and docking and other biochemical data we will model the interactions of the zymogen X with the TF.VIIa complex. We will also model the interactions of the kringle domains of plasminogen with this complex;
in Aim 5 we will develop models for the interaction of the cytoplasmic domain of the human tissue factor with ARP-280 (actin binding protein 280), and other interactions that may be critical in internal cell signaling events.
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