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1. Blacklock, Kristin, 1991-. New tools and approaches for computational protein design.
Degree: PhD, Quantitative Biomedicine, 2019, Rutgers University
This dissertation describes the development, benchmarking, validation, and application of computational methods, mostly written within the Rosetta suite of macromolecular modeling software, for the design and/or analysis of proteins. The introductory chapter brings the reader into the historical context of computational protein design, while detailing important concepts referenced in subsequent chapters. The second chapter is comprised of a benchmarking study of “LooDo”, a computational algorithm for the design of novel nested-domain proteins, which are proteins where one domain is inserted into another. This algorithm, named after its primary sampling method of loop-directed domain placement, was shown to be able to recapitulate native domain orientations for a benchmark set of five nested-domain proteins, as well as recapitulate domain-domain interface sequences and rank native versus nonnative domain combinations highly. In the next chapter, to improve the therapeutic ratio of the yeast cytosine deaminase (yCD)/5-fluorocytosine (5FC) directed-enzyme prodrug therapy system for targeted chemotherapy, we hypothesized that light-induced structural changes in yCD via bifunctional azobenzene derivative cross-linking would allow for the design of a photoswitchable yCD enzyme. Using generalizable computational design methods and experimental validation, we present one such design that allowed for a roughly 2-fold increase in activity towards cytosine under UV versus blue light stimuli. The fourth chapter presents a study in which the Rosetta and Amber energy functions are systematically compared by their performance in two structural evaluation tests and afterwards combined to increase the overall performance over both individually. The minimum-sum-of-ranks method employed in this chapter reduces the RMSD of the selected decoy by 1Å in 14 cases for the ff14SBonlySC energy function in Amber and 13 cases for the current Rosetta energy function, REF2015, in a large decoy discrimination benchmark test. The final chapter investigates bioisosteric alternatives to Axitinib in order to reduce the metabolic vulnerability of the heteroaryl thioether group. Using QM calculations, Rosetta docking protocols, and Amber molecular dynamics simulations, this study computationally evaluates four proposed structures by their predicted behaviors within the VEGFR2 kinase and ABL1 T315I gatekeeper mutant kinase binding pockets. Together, the work herein represents a collection of developments in the fields of computational biology and protein design.Advisors/Committee Members: Khare, Sagar D (chair), Case, David (internal member), Montelione, Gaetano (internal member), Nanda, Vikas (internal member), Woolley, G. Andrew (outside member), School of Graduate Studies.
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APA (6th Edition):
Blacklock, Kristin, 1. (2019). New tools and approaches for computational protein design. (Doctoral Dissertation). Rutgers University. Retrieved from https://rucore.libraries.rutgers.edu/rutgers-lib/60017/
Chicago Manual of Style (16th Edition):
Blacklock, Kristin, 1991-. “New tools and approaches for computational protein design.” 2019. Doctoral Dissertation, Rutgers University. Accessed July 15, 2020. https://rucore.libraries.rutgers.edu/rutgers-lib/60017/.
MLA Handbook (7th Edition):
Blacklock, Kristin, 1991-. “New tools and approaches for computational protein design.” 2019. Web. 15 Jul 2020.
Blacklock, Kristin 1. New tools and approaches for computational protein design. [Internet] [Doctoral dissertation]. Rutgers University; 2019. [cited 2020 Jul 15]. Available from: https://rucore.libraries.rutgers.edu/rutgers-lib/60017/.
Council of Science Editors:
Blacklock, Kristin 1. New tools and approaches for computational protein design. [Doctoral Dissertation]. Rutgers University; 2019. Available from: https://rucore.libraries.rutgers.edu/rutgers-lib/60017/