The impact of mRNA modifications on ribosomal decoding: a molecular dynamics simulation study

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dc.contributor.authorLea, Mark J.
dc.contributor.authorUniversity of Lethbridge. Faculty of Arts and Science
dc.contributor.supervisorWetmore, Stacey D.
dc.date.accessioned2025-09-02T19:37:05Z
dc.date.available2025-09-02T19:37:05Z
dc.date.issued2025
dc.degree.levelMasters
dc.description.abstractPost-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.description.sponsorshipNatural Sciences and Engineering Research Council of Canada (NSERC), Canada Graduate Scholarships - Master's (CGS-M) Alberta Innovates Graduate Student Scholarship Master's RNA Innovation Trainee Award University of Lethbridge Graduate Research Award (ULGRA)
dc.embargoNo
dc.identifier.urihttps://hdl.handle.net/10133/7121
dc.language.isoen
dc.publisherLethbridge, Alta. : University of Lethbridge, Dept. of Chemistry and Biochemistry
dc.publisher.departmentDepartment of Chemistry and Biochemistry
dc.publisher.facultyArts and Science
dc.relation.ispartofseriesThesis (University of Lethbridge. Faculty of Arts and Science)
dc.subjectmRNA modifications
dc.subjectribosomal decoding
dc.subjectpost-transcription
dc.subjectmRNA codon modifications
dc.subjecttranslation
dc.subject.lcshDissertations, Academic
dc.subject.lcshMessenger RNA--Research
dc.subject.lcshPost-translational modification--Research
dc.subject.lcshPost-translational modification--Mathematical models
dc.subject.lcshMolecular dynamics
dc.subject.lcshProteins--Synthesis--Research
dc.titleThe impact of mRNA modifications on ribosomal decoding: a molecular dynamics simulation study
dc.typeThesis
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