Show simple item record

FieldValueLanguage
dc.contributor.authorYasmin, Sabina
dc.date.accessioned2018-10-18
dc.date.available2018-10-18
dc.date.issued2018-03-29
dc.identifier.urihttp://hdl.handle.net/2123/18907
dc.description.abstractThe voltage activated potassium channel Kv1.3 is an important therapeutic target due to its vital role in the treatment of autoimmune diseases. A family of plant toxins identified recently but their binding affinities for Kv1 channels have not been characterized. Here we have studied the binding of four plant toxins EgK1, SmK1, JrK1, and CcK1 with Kv1 channels using molecular docking and molecular dynamics (MD) simulations. The EgK1 toxin has been found as a potent blocker of Kv1.3 and highly selective for Kv1.3 over Kv1.1. Umbrella sampling MD simulations are performed for the Kv1.3–EgK1 complex to calculate binding free energy. The binding modes of all toxins are compared to design an EgK1 analog with higher affinity for Kv1.3 which could be a potential therapeutic lead for the treatment of autoimmune diseases. Herceptin is used in the treatment of breast cancer for patients whose tumors excessively express the HER2 protein. Here we have performed a computational study of HER2–herceptin-Fab complex and identified three mutations on herceptin to increase its binding affinity for HER2. Using MD simulations and Free energy perturbation method, D28R mutation found as the most promising one for improving the binding affinity of herceptin for HER2. Aggregation of protein is an undesired phenomena which reduces the antibody activity, so it is vitally necessary to understand the mechanism of aggregation at a molecular level for designing aggregation resistant versions of therapeutic antibodies. Here, we use higher temperature MD simulations to identify the aggregation prone regions in an antibody with a crystal structure (1HZH). The role of glycosylation in 1HZH is found to increase the overall stability of the antibody. The identified aggregation prone regions are modified via mutations to increase the aggregation resistance of the antibody.en_AU
dc.rightsThe author retains copyright of this thesis. It may only be used for the purposes of research and study. It must not be used for any other purposes and may not be transmitted or shared with others without prior permission.en_AU
dc.subjectPotassium channelsen_AU
dc.subjectMolecular dynamicsen_AU
dc.subjectPotential of mean forceen_AU
dc.subjectMolecular dockingen_AU
dc.subjectFree energy perturbationen_AU
dc.subjectantibody aggregationen_AU
dc.titleComputational Studies of Plant Toxin Blockers of Potassium Channels, and Affinity & Aggregation of Antibodiesen_AU
dc.typeThesisen_AU
dc.description.embargo2020-03-04
dc.type.thesisDoctor of Philosophyen_AU
usyd.facultyFaculty of Science, School of Physicsen_AU
usyd.degreeDoctor of Philosophy Ph.D.en_AU
usyd.awardinginstThe University of Sydneyen_AU


Show simple item record

Associated file/s

Associated collections

Show simple item record

There are no previous versions of the item available.