Protein-protein interactions have historically been branded “undruggable” due to their intrinsic challenges above and beyond protein-small molecule interactions. Incrementally, system after system has been approached by a variety of specialized design strategies. Still, the vast majority of interactions are intractable, and the profusion of individualized strategies leave few general approaches that might be able to extend to recalcitrant systems.
The ecosystem of tools available for developing inhibitors of protein-protein interactions suggests a potential modular strategy for proceeding from protein structure to plausible interaction inhibitors. My dissertation describes an analysis of all the protein-protein interactions containing key interfacial structural motifs found in protein structures catalogued by the Protein Data Bank. This work provides both data on extant protein interactions and specific conclusions regarding directions for further peptidomimetic design. We describe the incorporation of our lab’s peptidomimetic scaffolds into Rosetta and the validation of those methods against valuable biological systems. Finally, I chronicle substantial extension to Rosetta’s capacity to accurately model and design peptidomimetic structures.
|Advisor:||Arorar, Paramjit S.|
|Commitee:||Bonneau, Richard, Kallenbach, Neville, Woerpel, Keith, Zhang, Yingkai|
|School:||New York University|
|School Location:||United States -- New York|
|Source:||DAI-B 78/04(E), Dissertation Abstracts International|
|Subjects:||Chemistry, Biochemistry, Biophysics|
|Keywords:||Helical mimetics, Inhibitor design, Interface design, Peptidomimetics, Protein-protein interaction|
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