Date of Award

8-2016

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Legacy Department

Chemistry

Committee Member

Dr. Brian Dominy, Committee Chair

Committee Member

Dr. Steve Stuart

Committee Member

Dr. Emil Alexov

Committee Member

Dr. Julia Brumaghim

Abstract

Physiology signals can be passed by proteins. Many protein signaling starts from ligand binding and undergoes conformation change of the receptors. Many cellular surface receptor proteins contain a Von Willebrand factor (vWF), which is a large multimeric glycoprotein present in blood plasma. This dissertation employed molecular dynamics (MD) simulation to investigate the binding and signaling process of several vWF type A proteins. Chapter 2 discussed the potential errors modeling and MD sampling methods, and evaluated the accuracy and precision of free energy calculation. An optimized sampling strategy was established to obtain the best computational efficiency. The strategy can be applied to a wide range of protein binding research. The following chapters investigated the binding and signaling process of anthrax receptors and integrins, which are vWF type A proteins. Binding mechanism, possibility of conformational change, and the role of metal ion in binding process, were analyzed and compared for two structurally highly similar anthrax receptor proteins, tumor endothelial marker 8 (TEM8) and capillary morphogenesis gene 2 (CMG2). The two highly similar proteins are the drug target for distinct diseases. The differences in these two processes were found can guide the further development of drug specifically targeting one of the proteins. A conformation change between open and closed conformation is known to exist in most vWF type A proteins, but has not been experimentally observed in the anthrax receptors. Chapter 5 investigated the binding and conformation change process of integrins using targeted molecular dynamics simulation, and compared with anthrax receptors. The key residues and correlated motions in conformation change process were revealed, which can serve as a reference to the development in small molecule inhibitors of the signaling process. Results further confirmed the difficulties of observing conformation change in anthrax receptors.

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