Estudo de modificações de RNA através de modelos mesoscópicos: inosina e pseudouridina
RNA modifications are small chemical changes that occur in their nitrogenous bases, leading to alterations in physical, chemical, and structural properties. Currently, more than 150 naturally occurring RNA modifications are known. These modifications are often essential for the proper functioning of...
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| Tipo de recurso: | tesis de maestría |
| Estado: | Versión publicada |
| Fecha de publicación: | 2025 |
| País: | Brasil |
| Institución: | Universidade Federal de Minas Gerais (UFMG) |
| Repositorio: | Repositório Institucional da UFMG |
| Idioma: | portugués |
| OAI Identifier: | oai:repositorio.ufmg.br:1843/80617 |
| Acceso en línea: | http://hdl.handle.net/1843/80617 |
| Access Level: | acceso abierto |
| Palabra clave: | RNA modificado Modelos mesoscópicos Temperatura de desnaturação Bases modificadas Ácido ribonucleico |
| Sumario: | RNA modifications are small chemical changes that occur in their nitrogenous bases, leading to alterations in physical, chemical, and structural properties. Currently, more than 150 naturally occurring RNA modifications are known. These modifications are often essential for the proper functioning of various cellular mechanisms and for the correct development of complex organisms. Furthermore, modified nucleic acids can be used in a wide range of biotechnological techniques, such as RT-PCR, drug delivery protocols, and mRNA vaccines. Inosine (I) results from the deamination of adenine (A) due to the action of three enzymes from the adenosine deaminase family acting on RNA (ADAR). In mRNA, inosine is usually recognized by the ribosome as guanosine (G), which can result in non-synonymous protein translation, contributing to epigenetic variability. The irregular presence of inosine in the RNA molecule is associated with several diseases, especially neurodegenerative cognitive diseases such as Alzheimer’s. Pseudouridine ($\Psi$) is an isomer of uridine (U) and the most frequently found modification in RNA molecules, being present in mRNA, tRNA, and other RNA types. Its occurrence results from the action of various enzymes that act highly specifically on RNA sequences. One of the main functions of pseudouridine is to stabilize the secondary structures of complex RNAs, such as tRNA and rRNA. N1-methylpseudouridine (m$^1\Psi$) results from the methylation of pseudouridine and has been widely used in mRNA vaccines as a substitute for uridine. In this work, we used the nearest-neighbor (NN) model and the Peyrard-Bishop (PB) mesoscopic model to study the contribution of inosine, pseudouridine, and N1-methylpseudouridine to the thermodynamic stability of RNA duplexes. The NN model describes this stability through the energetic contributions of each base pair. In contrast, the PB model, a statistical physics model, considers hydrogen bonds and stacking interactions between base pairs and their neighbors for the thermodynamic stability of the duplex. Parameters related to these interactions were obtained for modified RNA sequences. Melting temperatures of 71 RNA sequences containing inosine, 41 with pseudouridine, and 9 with N1-methylpseudouridine were analyzed. Our results suggest that these modifications can stabilize the RNA duplex. This stability provided by the modifications generally depends on the sequence context in which they are inserted, potentially contributing negatively or positively to duplex stability. Inosine shows a tendency to destabilize the duplex. In particular, the IU pair shows the presence of only one hydrogen bond. In general, pairs with pseudouridine act to stabilize the duplex. N1-methylpseudouridine behaves similarly to pseudouridine and shows stronger interaction with neighbors. The thermodynamic parameters obtained for these three RNA modifications may contribute, using the calculation of melting temperatures and opening profiles, to the design of probes in diagnostics and also the development of RNA-based vaccines. |
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