RNA therapeutics by design - optimising mRNA structures by advanced computation to improve therapeutics and vaccine formulations

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Messenger RNAs (mRNAs) are long single-stranded RNAs that can span up to thousands of nucleotides. Recently, cryo-electron microscopy and chemical probing experiments have shown that mRNAs may adopt various structures in vitro and in vivo. Although the details of these structures are still elusive due to their flexibility and heterogeneity, it has been suggested that some regions of mRNAs, such as untranslated regions, form specific structures to regulate protein translation. Further elucidation of such regulatory mechanisms requires understanding of the structures. In addition, mRNAs have a great potential for therapeutic application, as evidenced by the success of COVID-19 mRNA vaccines. However, it is rather surprising that almost nothing is known about the structure of mRNA in these formulations; a better understanding of the structure of mRNA in lipid nanoparticles and polymer-based delivery systems is essential for the further application of mRNA therapeutics.This PhD project aims to establish a molecular simulation model suitable for long single-stranded RNA to reveal structural ensembles of mRNAs. With support from the experienced and multidisciplinary supervisory team, the successful candidate will develop a novel computational approach for mRNA structures based on existing coarse-grained molecular models. After validating the model with bioinformatics and experimental data, we will further investigate mRNA structures under conditions of polymer-based vaccine formulations. We will seek better strategies to design RNA therapeutics in silico.