Date of Award
Steven W. Rick
Molecular Dynamics simulations are a highly useful tool in helping understand the fundamental interactions present in a variety of chemical systems. The work discussed here illustrates it’s use in determining the conformational dynamics of the Zika and SARS-Cov-2 helicase in a physiological environment, largely in an effort to discover inhibitors capable of rendering the protein inert. Additionally, we show how it can be used to understand paradoxical trends in the anion-induced precipitation of Cucurbituril cavitands.
Viral helicases are motor proteins tasked with unwinding the viral dsRNA, a crucial step in preparing the strand to be translatable by host cells. By virtue of this function, it is vital and necessary for the pathogen to replicate and successfully carry the infection forward. Given this role, helicases are now becoming a topic of many research efforts primarily centered around the discovery of compounds targeting these enzymes. Through a combination of drug docking, molecular dynamics simulations, and the computation of binding energies, these studies revealed a list of potential inhibitors of the helicases of both the Zika virus and the SARS-Cov-2 virus responsible for causing COVID-19.
Cucurbiturils are widely studied cavitands that readily encapsulate smaller molecules, forming ”host-guest” inclusion complexes with charged, yet predominantly hydrophobic guests. The 7-monomer macrocycle (CB7) is of particular interest given its high solubility in aqueous solutions, making it one of the more investigated cavitands in modern supramolecular chemistry. These studies aimed to better understand how these complexes behave in ionic solutions. Specifically, molecular dynamics simulations were performed to explain current paradigms in the Hofmeister series when precipitating CB7. The data revealed that hexafluorophosphate is most likely to bind at the charged crowns (likely neutralizing it and promoting crystallization), while iodide associated mostly with the exterior, hydrophobic surfaces of CB7 (likely increasing the solubility). Both findings are consistent with experimentally derived critical precipitation concentrations (CPC) of these anions, serving as a reliable explanation for their deviations from the traditional Hofmeister series.
Raubenolt, Bryan, "Applied Molecular Dynamics: from Targeting Viral Helicases, to Understanding the Interactions of Cucurbituril Complexes in Ionic Solutions" (2020). University of New Orleans Theses and Dissertations. 2841.
Available for download on Saturday, December 18, 2021
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