Fogarty, Rebekah Joy2024-12-202024-12-202024-12-19vt_gsexam:42259https://hdl.handle.net/10919/123856G-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.ETDenIn CopyrightG-QuadruplexMolecular DynamicsComputer-Aided Drug DesignThesis