Orbital overlap as a tool in computational design of molecules
Jones, Stephanie Ing
Jones, Stephanie Ing
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Date
2019
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Abstract
There are two different aspects to this project, design and tool, which are later combined and applied to a final project to study protein binding sites. The first design aspects focus on building a receptor that will bind to trimethylamine N-oxide (TMAO) in the body. Studies have shown that higher levels of TMAO increases the risk of cardiovascular diseases (CVD) and atherosclerosis. Here, a receptor is computationally built based on the binding between TorT and TMAO. The second design project is on lignin. In the pulping and biorefinery processes, lignin is disposed as a waste stream after lignocelluloses other components (hemicellulose and cellulose) are extracted. Substituent effects of β-o-4 linkages were studied on lignin models along two reaction pathways: SN2 and E1. The last design project is on warfarin, which is the medicine of choice when it comes to treating blood clots since 1955.^One of the many reasons for dosage variance is due to the makeup of each patients vitamin K epoxide reductase (VKOR) enzyme, which has been shown to mutate. To this day, human VKOR (hVKOR) has not been crystallized, and there have been ongoing disagreements on its structure and warfarins binding site. This study predicts hVKOR structure and the docking site for warfarin. The tool used here is the orbital overlap distance function D(r2), which quantifies the size of molecular orbitals of system being studied. Chemically hard species with tightly bound electrons tend to have a smaller D(r2) than a soft species with loosely bound electrons. Here, the orbital overlap distance is tested on F centers, which are singly occupied electron systems. Orbital overlap distance function is also applied onto protein binding sites and ligands.^Typical analysis of protein molecules involves electrostatic and hydrophobic interaction maps, but the addition of the orbital overlap distance would be a useful tool to rationalize noncovalent interactions in a proteins active site. In this study, a combination of D(r2) and molecular electrostatic potential are used to rationalize noncovalent interactions in a proteins active site. These studies can then be applied to designing an alternative drug to warfarin; where D(r2) can justify whether warfarin and vitamin K 2,3-epoxide would bind to the predicted binding site.
Contents
Subject
Subject(s)
Molecular orbitals.
Molecules Models.
Protein binding.
Molecules Models.
Protein binding.
Research Projects
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Dissertation
Description
Format
1 online resource (xviii, 120 pages) :
Department
Chemistry and Biochemistry