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You searched for +publisher:"Washington University in St. Louis" +contributor:("David Sept"). Showing records 1 – 2 of 2 total matches.

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Washington University in St. Louis

1. Wong, Diana. The Interaction of Cofilin with the Actin Filament.

Degree: PhD, Biomedical Engineering, 2011, Washington University in St. Louis

The regulation of filamentous actin: F-actin) production from the polymerization of globular actin: G-actin) within the cell is critical for many cell functions. Since actin is found in all cells, understanding how actin-binding-proteins: ABPs) bind and how their regulating mechanisms work is not only important to the basics of cytoskeletal pathways, but also to understanding associated diseases and creating possible therapeutics to combat them. Cofilin is an ABP that plays an important part in the regulation process and in recent times, has come to be known as a player in maintaining a cell's homeostasis. It's activity has been shown to have implications in many diseases, such as Alzheimer's and certain cancers. Cofilin binds and severs actin filaments, leading to depolymerization as well as the creation of new barbed ends. Although some of the details of cofilin's interaction with G-actin have been illuminated through a range of experimental studies, the specific interactions with F-actin have remained much more elusive. As of yet, there are only cryoEM models of cofilin-bound F-actin: where the binding occurs at a 1:1 ratio), which are not high enough resolution and do not show molecular interactions. The focus of this research is to build a model of how cofilin binds F-actin and understand the mechanism of severing. Computational methods, such as protein-protein docking, all atom molecular dynamics: AA MD) simulations, and Coarse Grain MD: CG MD) can help in understanding the interactions between cofilin and F-actin. Iteratively combining these methods with biochemical and mutagenesis experiments to reach a consensus offer a guide towards a more cogent answer. Here in this dissertation, I describe how I built a cofilin and F-actin binding model, with the aid of empirical data. This work allowed me to create several filament models with varying number of bound cofilin, which replicates different binding states of the filament. I also simulated the dynamics of these filaments models to gain insight into filament behavior, particularly twist. Advisors/Committee Members: David Sept.

Subjects/Keywords: Biophysics; Bioinformatics; Biomedical Engineering; cofilin; computational structural biology; docking models; F-actin; filament dynamics; molecular dynamics simulations

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6th Edition):

Wong, D. (2011). The Interaction of Cofilin with the Actin Filament. (Doctoral Dissertation). Washington University in St. Louis. Retrieved from https://openscholarship.wustl.edu/etd/902

Chicago Manual of Style (16th Edition):

Wong, Diana. “The Interaction of Cofilin with the Actin Filament.” 2011. Doctoral Dissertation, Washington University in St. Louis. Accessed August 10, 2020. https://openscholarship.wustl.edu/etd/902.

MLA Handbook (7th Edition):

Wong, Diana. “The Interaction of Cofilin with the Actin Filament.” 2011. Web. 10 Aug 2020.

Vancouver:

Wong D. The Interaction of Cofilin with the Actin Filament. [Internet] [Doctoral dissertation]. Washington University in St. Louis; 2011. [cited 2020 Aug 10]. Available from: https://openscholarship.wustl.edu/etd/902.

Council of Science Editors:

Wong D. The Interaction of Cofilin with the Actin Filament. [Doctoral Dissertation]. Washington University in St. Louis; 2011. Available from: https://openscholarship.wustl.edu/etd/902


Washington University in St. Louis

2. Saxena, Akansha. Structural and Functional Studies on BK(Ca) Channels.

Degree: PhD, Biomedical Engineering, 2010, Washington University in St. Louis

The long term goal of this research is to study the structure and function of the BKCa channels, by focusing on the effect of a single residue mutation, the epilepsy mutation. BKCa channels are potassium channels, activated by voltage, Ca2+ and Mg2+ ions. These factors control the opening and closing of the channel pore and thus regulate the large K+ current passing through them. Recently, a mutation D434G in humans, was found to make the channel hyperactive and more sensitive to the Ca2+ ions. The single residue mutation, resulting from a substitution of an Asp to Gly, was found to be linked with epilepsy and paroxysmal dyskinesia. The central focus of this thesis is to identify the molecular mechanism behind the structural and functional changes caused by this mutation. Using comparative modeling and molecular dynamics simulations, it is revealed that the epilepsy mutation reduces the flexibility of the channel protein and drives it to a rigid conformation. The loss in dynamics is seen around the Ca2+ binding site which reflects its direct impact on the Ca2+ activation of the channel. Comparison with experimental results show that the change in dynamics is targeted to regions which possibly connects the Ca2+ –binding site to the pore and thus transfer this effect to the pore. The thesis also presents a new method of representation of cations in computational techniques, the multisite cation model. The model presents improvement in the reproduction of accurate structural and thermodynamical properties of ion–mediated mechanisms. The successful implementation of the model in protein and water systems show that the model will prove very useful in increasing the accuracy and precision of metal mediated simulations and energy calculations. Advisors/Committee Members: David Sept.

Subjects/Keywords: Biomedical Engineering; Biophysics; Computational Biophysics, Homology Modeling, Molecular Dynamics, Molecular Modeling

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6th Edition):

Saxena, A. (2010). Structural and Functional Studies on BK(Ca) Channels. (Doctoral Dissertation). Washington University in St. Louis. Retrieved from https://openscholarship.wustl.edu/etd/311

Chicago Manual of Style (16th Edition):

Saxena, Akansha. “Structural and Functional Studies on BK(Ca) Channels.” 2010. Doctoral Dissertation, Washington University in St. Louis. Accessed August 10, 2020. https://openscholarship.wustl.edu/etd/311.

MLA Handbook (7th Edition):

Saxena, Akansha. “Structural and Functional Studies on BK(Ca) Channels.” 2010. Web. 10 Aug 2020.

Vancouver:

Saxena A. Structural and Functional Studies on BK(Ca) Channels. [Internet] [Doctoral dissertation]. Washington University in St. Louis; 2010. [cited 2020 Aug 10]. Available from: https://openscholarship.wustl.edu/etd/311.

Council of Science Editors:

Saxena A. Structural and Functional Studies on BK(Ca) Channels. [Doctoral Dissertation]. Washington University in St. Louis; 2010. Available from: https://openscholarship.wustl.edu/etd/311

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