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

信使rna （mrna）是长单链rna，可以跨越数千个核苷酸。近年来，低温电子显微镜和化学探针实验表明，mrna在体外和体内可能采用多种结构。尽管由于其灵活性和异质性，这些结构的细节仍然难以捉摸，但有人认为mrna的某些区域，如非翻译区域，形成特定的结构来调节蛋白质翻译。进一步阐明这种调节机制需要了解结构。此外，mRNA具有巨大的治疗应用潜力，COVID-19 mRNA疫苗的成功证明了这一点。然而，令人惊讶的是，在这些分子式中对mRNA的结构几乎一无所知；更好地了解mRNA在脂质纳米颗粒和基于聚合物的递送系统中的结构对于mRNA治疗的进一步应用至关重要。本博士项目旨在建立适合于长单链RNA的分子模拟模型，揭示mrna的结构集合体。在经验丰富的多学科管理团队的支持下，成功的候选人将基于现有的粗粒度分子模型开发一种新的mRNA结构计算方法。在用生物信息学和实验数据验证模型后，我们将进一步研究基于聚合物的疫苗配方条件下的mRNA结构。我们将寻求更好的策略来设计RNA治疗方法。

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.