Polarizable Simulations of the bcl-2 DNA G-Quadruplex and FMRP RNA G-Quadruplex:Duplex Junction Binding Protein
| dc.contributor.author | Ratnasinghe, Brian Damith | en |
| dc.contributor.committeechair | Lemkul, Justin A. | en |
| dc.contributor.committeemember | Brown, Anne M. | en |
| dc.contributor.committeemember | Jutras, Brandon L. | en |
| dc.contributor.department | Biochemistry | en |
| dc.date.accessioned | 2022-11-26T07:00:22Z | en |
| dc.date.available | 2022-11-26T07:00:22Z | en |
| dc.date.issued | 2021-06-03 | en |
| dc.description.abstract | A G-quadruplex (GQ) is a type of noncanonical nucleic acid structure that can form in regions of nucleic acids rich in guanine nucleotides. The guanine bases form a square planar conformation via Hoogsteen hydrogen bonding. These stacked tetrads have inward-facing carbonyl oxygens, facilitating the coordination of ions. Improper GQ conformations can lead to improper regulation of gene expression, potentially resulting in genetic diseases or cancer. Here, we performed molecular dynamics simulations using the Drude polarizable force field (FF) to gain insight into factors contributing to the stability of two GQs. One is the bcl-2 promoter region GQ, which is implicated in several types of cancer including B-cell lymphoma, and the second is the sc1 RNA GQ, which binds to the Fragile-X Mental Retardation Protein (FMRP) and is implicated in the development of Fragile X Syndrome (FXS). Aberrant bcl-2 GQ conformations result in increased production of the BCL2 protein, which is an apoptosis inhibitor. As such, we aim to characterize the factors stabilizing the GQ for future small-molecule development to prevent apoptosis inhibition and therefore cancer. The FMRP protein functions as a regulator of sc1 conformation to control the translation of proteins required for frontal lobe development. FXS arises from a nonsense mutation that causes the deletion of the C-terminal region of FMRP, rendering it non-function. Therefore, we aim to simulate sc1 when FMRP is bound as well as unbound to provide insight into the types of interactions that must be maintained and therefore mimicked by a small molecule drug. | en |
| dc.description.abstractgeneral | DNA is commonly represented as a double helix and RNA is thought of as a simple single stranded, disordered molecule, but DNA and RNA can both adopt more complicated structures. An example of this is the G-quadruplex (GQ), a structure that can form in regions of DNA and RNA that are rich in guanine. These guanine bases form a stable core structure that can act as an "on-off" switch for different processes in the cell. Alterations to GQ structure can lead to dysfunction and different types of disease. Here, we perform atomistic computer simulations to further understand factors that contribute to GQ stability, focusing on two different GQs, one of plays a role in several types of cancer, and the other whose regulation is in Fragile X Syndrome (FXS). Furthermore, we study the Fragile X Mental Retardation Protein, which is what brain cells normally use to regulate expression of proteins needed for frontal lobe development by modulating specific GQ structure. The information from these simulations can be used to potentially develop drugs for these conditions. | en |
| dc.description.degree | Master of Science in Life Sciences | en |
| dc.format.medium | ETD | en |
| dc.identifier.other | vt_gsexam:31209 | en |
| dc.identifier.uri | http://hdl.handle.net/10919/112699 | en |
| dc.publisher | Virginia Tech | en |
| dc.rights | In Copyright | en |
| dc.rights.uri | http://rightsstatements.org/vocab/InC/1.0/ | en |
| dc.subject | G-quadruplex | en |
| dc.subject | Molecular Dynamics | en |
| dc.subject | Classical Drude Oscillator | en |
| dc.subject | Electronic Polarization | en |
| dc.title | Polarizable Simulations of the bcl-2 DNA G-Quadruplex and FMRP RNA G-Quadruplex:Duplex Junction Binding Protein | en |
| dc.type | Thesis | en |
| thesis.degree.discipline | Biochemistry | en |
| thesis.degree.grantor | Virginia Polytechnic Institute and State University | en |
| thesis.degree.level | masters | en |
| thesis.degree.name | Master of Science in Life Sciences | en |