{"id":{"repo_id":"lethbridge","oai_identifier":"oai:opus.uleth.ca:10133/7121"},"canonical_url":"https://search.dev.ndltd.org/etd/lethbridge/oai:opus.uleth.ca:10133/7121","repository":{"repo_id":"lethbridge","name":"University of Lethbridge","base_url":"https://opus.uleth.ca/server/oai/request"},"display":{"title":"The impact of mRNA modifications on ribosomal decoding: a molecular dynamics simulation study","abstract":"Post-transcriptional RNA modifications are key regulators of translational accuracy and efficiency. While ribosomal RNA (rRNA) and transfer RNA (tRNA) modifications have well-characterized roles in protein synthesis, the functions of messenger RNA (mRNA) codon modifications are less understood. However, growing evidence suggests that mRNA codon modifications can modulate translation. Naturally occurring mRNA modifications can be enzymatically added, such as inosine (I), which is incorporated into mRNA codons to expand decoding capacity and remodel the proteome. Alternatively, modifications can result from damage to mRNA codons, such as the alkylative lesions 1-methylguanosine (m1G) and 2-methylguanosine (m2G), which can have potentially unpredictable and harmful consequences. This thesis developed a large-scale computational model of the ribosomal A-site (>370,000 atoms) and performed molecular dynamics (MD) simulations to understand the position-dependent structural effects of the inosine, m1G, and m2G codon modifications. These investigations revealed that modified codons associated with experimentally-observed reduced peptide formation rates exhibit tRNA dissociation or distorted decoding center geometries. In contrast, modified codons with negligible effects on experimental rates maintain A-site conformations that promote productive decoding. Thus, this thesis provides mechanistic insight into how mRNA modifications can regulate translation at the atomic level and establishes a robust computational method for future studies that strive to understand the roles of numerous additional RNA modifications during translation.","abstract_html":"Post-transcriptional RNA modifications are key regulators of translational accuracy and efficiency. While ribosomal RNA (rRNA) and transfer RNA (tRNA) modifications have well-characterized roles in protein synthesis, the functions of messenger RNA (mRNA) codon modifications are less understood. However, growing evidence suggests that mRNA codon modifications can modulate translation. Naturally occurring mRNA modifications can be enzymatically added, such as inosine (I), which is incorporated into mRNA codons to expand decoding capacity and remodel the proteome. Alternatively, modifications can result from damage to mRNA codons, such as the alkylative lesions 1-methylguanosine (m1G) and 2-methylguanosine (m2G), which can have potentially unpredictable and harmful consequences. This thesis developed a large-scale computational model of the ribosomal A-site (>370,000 atoms) and performed molecular dynamics (MD) simulations to understand the position-dependent structural effects of the inosine, m1G, and m2G codon modifications. These investigations revealed that modified codons associated with experimentally-observed reduced peptide formation rates exhibit tRNA dissociation or distorted decoding center geometries. In contrast, modified codons with negligible effects on experimental rates maintain A-site conformations that promote productive decoding. Thus, this thesis provides mechanistic insight into how mRNA modifications can regulate translation at the atomic level and establishes a robust computational method for future studies that strive to understand the roles of numerous additional RNA modifications during translation.","abstract_has_math":false,"creators":["Lea, Mark J.","University of Lethbridge. Faculty of Arts and Science"],"institution":null,"degree_name":null,"degree_level":null,"degree_discipline":null,"degree_department":null,"school":null,"contributors":[],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2025,"date_issued":"2025","date_published":"2025","updated_at":"2026-07-27T20:02:29Z","subjects":["mRNA modifications","ribosomal decoding","post-transcription","mRNA codon modifications","translation"],"languages":[],"rights":[],"rights_urls":[],"identifier_entries":[{"key":"dc:identifier","label":"Identifier","values":["hdl:10133/7121"],"render_values":[{"text":"hdl:10133/7121","href":null,"code":true}]}]},"links":{"outbound_url":null,"outbound_label":null,"outbound_source":null},"metadata_groups":[{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.issued","label":"Date","values":["2025"]},{"key":"dc:type","label":"Dc Type","values":["Thesis"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["mRNA modifications","ribosomal decoding","post-transcription","mRNA codon modifications","translation"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["hdl:10133/7121"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.other","label":"Dc Description Other","values":["Post-transcriptional RNA modifications are key regulators of translational accuracy and efficiency. While ribosomal RNA (rRNA) and transfer RNA (tRNA) modifications have well-characterized roles in protein synthesis, the functions of messenger RNA (mRNA) codon modifications are less understood. However, growing evidence suggests that mRNA codon modifications can modulate translation. Naturally occurring mRNA modifications can be enzymatically added, such as inosine (I), which is incorporated into mRNA codons to expand decoding capacity and remodel the proteome. Alternatively, modifications can result from damage to mRNA codons, such as the alkylative lesions 1-methylguanosine (m1G) and 2-methylguanosine (m2G), which can have potentially unpredictable and harmful consequences. This thesis developed a large-scale computational model of the ribosomal A-site (>370,000 atoms) and performed molecular dynamics (MD) simulations to understand the position-dependent structural effects of the inosine, m1G, and m2G codon modifications. These investigations revealed that modified codons associated with experimentally-observed reduced peptide formation rates exhibit tRNA dissociation or distorted decoding center geometries. In contrast, modified codons with negligible effects on experimental rates maintain A-site conformations that promote productive decoding. Thus, this thesis provides mechanistic insight into how mRNA modifications can regulate translation at the atomic level and establishes a robust computational method for future studies that strive to understand the roles of numerous additional RNA modifications during translation."]},{"key":"dc:title","label":"Title","values":["The impact of mRNA modifications on ribosomal decoding: a molecular dynamics simulation study"]}]}],"canonical_facts":{"dc:date.issued":["2025"],"dc:description.other":["Post-transcriptional RNA modifications are key regulators of translational accuracy and efficiency. While ribosomal RNA (rRNA) and transfer RNA (tRNA) modifications have well-characterized roles in protein synthesis, the functions of messenger RNA (mRNA) codon modifications are less understood. However, growing evidence suggests that mRNA codon modifications can modulate translation. Naturally occurring mRNA modifications can be enzymatically added, such as inosine (I), which is incorporated into mRNA codons to expand decoding capacity and remodel the proteome. Alternatively, modifications can result from damage to mRNA codons, such as the alkylative lesions 1-methylguanosine (m1G) and 2-methylguanosine (m2G), which can have potentially unpredictable and harmful consequences. This thesis developed a large-scale computational model of the ribosomal A-site (>370,000 atoms) and performed molecular dynamics (MD) simulations to understand the position-dependent structural effects of the inosine, m1G, and m2G codon modifications. These investigations revealed that modified codons associated with experimentally-observed reduced peptide formation rates exhibit tRNA dissociation or distorted decoding center geometries. In contrast, modified codons with negligible effects on experimental rates maintain A-site conformations that promote productive decoding. Thus, this thesis provides mechanistic insight into how mRNA modifications can regulate translation at the atomic level and establishes a robust computational method for future studies that strive to understand the roles of numerous additional RNA modifications during translation."],"dc:identifier":["hdl:10133/7121"],"dc:subject":["mRNA modifications","ribosomal decoding","post-transcription","mRNA codon modifications","translation"],"dc:title":["The impact of mRNA modifications on ribosomal decoding: a molecular dynamics simulation study"],"dc:type":["Thesis"]},"updated_at":"2026-07-27T20:02:29Z"}