Defense Date


Document Type


Degree Name

Doctor of Philosophy



First Advisor

Michael Peters


Understanding the energetic and dynamic behavior of natural protein fluctuations is critical to elucidating important information associated with a multitude of protein functions including signaling processes, enzyme behavior, aggregation pathways etc... This information is also critically important in the development of novel and effective strategies aimed at target proteins associated with pathologies and disease. In order to obtain such useful information, tools and techniques are lacking that: 1) permit the efficient quantitative analysis of fluctuation behavior of existing protein structure ensembles and 2) permit computationally generated natural fluctuation states of proteins at relatively large timescales demanded by the need for biologically relevant results. This thesis presents such methods as well as the results of their application to a case study of Aβ40 and pathogenic Aβ42 where we identify key differences in energy interactions between those two isoforms. Additionally, our detailed atom-level analysis, was able to identify very minute differences in Ramachandran angles between the two strains as the cause for these interaction energy differences. We also demonstrate the efficacy of our implicit solvent algorithm in recovering independently, experimentally identified domain motion over a variety of protein systems. Such a system that is medically significant is the HIV-1 protease for which we identified significant motion of a flap domain known to be pharmaceutically important to the protease’s active site in drug targeting strategies. Lastly, we employ the insights thus acquired from the Aβ40/42 case study to see if Aβ42 aggregation inhibitors can be rationally developed and then tested in vitro for their efficacy. Results were very promising with Aβ42 aggregate sizes being significantly reduced by statistically significant margins by the inhibitor compounds. Due to these encouraging results, we have consequently obtained a provisional patent application for our inhibitors.


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Available for download on Friday, July 01, 2022