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Structural Dynamics and Electrostatic Properties of the VEGF and PIM-1 Oncogenic Promoter G-Quadruplexes from Polarizable Molecular Dynamics Simulations

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dc.contributor.authorFogarty, Rebekah Joyen
dc.contributor.committeechairLemkul, Justin Alanen
dc.contributor.committeememberVinauger Tella, Clementen
dc.contributor.committeememberBrown, Anne M.en
dc.contributor.departmentBiochemistryen
dc.date.accessioned2024-12-20T09:01:30Zen
dc.date.available2024-12-20T09:01:30Zen
dc.date.issued2024-12-19en
dc.description.abstractG-Quadruplexes (GQs) are higher ordered nucleic acid structures that form within regions of DNA and RNA that are enriched with guanine nucleobases. These structures are highly stable and have been shown to function in genomic maintenance and regulating key biological processes. Due to their role in regulating gene expression, GQs also contribute to a wide variety of human diseases including neurodegenerative conditions, premature aging disorders, and various cancers. Therefore, these structures have gained growing interest as the subjects of various research investigations to explore potential methods for targeting and disease management on transcriptional and translational levels. However, targeting efforts have been relatively unsuccessful due to the conserved GQ core structure, leading to compounds that cannot bind to their targets with sufficient specificity. Here, we employed conventional and enhanced sampling molecular dynamics simulations on two oncogenic GQ structures with the Drude polarizable force field to gain crucial insights into structural and electrostatic properties contributing to overall GQ stability and potential small-molecule binding sites. In addition to these simulations, we also subjected these structures to the Site Identification by Ligand Competitive Saturation workflow to determine the favorability of various functional groups and gain insights into preferential binding of these GQ structures.en
dc.description.abstractgeneralGenetic mutations can contribute to diseases in individuals, including many cancers. Some genes are more likely to result in abnormal activity in cancerous cells; these genes are known as oncogenes. These genes provide a unique targeting opportunity for cancer therapeutic approaches by targeting cancers on the genomic level. G-Quadruplexes (GQs) form in DNA and RNA, using complex stacking and hydrogen bonding interactions to stabilize these structures. GQ-forming sequences have been identified in many oncogenes, in regulatory regions that dictate the expression of the genes. An emerging treatment strategy is to stabilize these GQs, thus reducing oncogene expression. Due to the similar structures adopted by the majority of these GQs, targeting them effectively has been a challenge in the field. Therefore, it is necessary to characterize the structural properties of GQs that govern their behaviors, to better understand how targeting approaches can be improved in future drug design efforts. In this study, we utilized computational techniques such as molecular dynamics (MD) simulations to gain insight into these properties of two oncogenic GQ structures. Additionally, we conducted simulations with common drug fragments to help further improve and inform drug design for these GQ structures.en
dc.description.degreeMaster of Science in Life Sciencesen
dc.format.mediumETDen
dc.identifier.othervt_gsexam:42259en
dc.identifier.urihttps://hdl.handle.net/10919/123856en
dc.language.isoenen
dc.publisherVirginia Techen
dc.rightsIn Copyrighten
dc.rights.urihttp://rightsstatements.org/vocab/InC/1.0/en
dc.subjectG-Quadruplexen
dc.subjectMolecular Dynamicsen
dc.subjectComputer-Aided Drug Designen
dc.titleStructural Dynamics and Electrostatic Properties of the VEGF and PIM-1 Oncogenic Promoter G-Quadruplexes from Polarizable Molecular Dynamics Simulationsen
dc.typeThesisen
thesis.degree.disciplineBiochemistryen
thesis.degree.grantorVirginia Polytechnic Institute and State Universityen
thesis.degree.levelmastersen
thesis.degree.nameMaster of Science in Life Sciencesen

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