Joint Design of 5' Untranslated Region and Coding Sequence of mRNA

TL;DR

This paper introduces LinearDesign2, an algorithm for the joint design of 5' UTR and coding sequence in mRNA to optimize translation efficiency and stability, outperforming previous methods.

Contribution

The study presents a novel co-design algorithm that simultaneously optimizes multiple mRNA features, advancing beyond existing single-region design approaches.

Findings

LinearDesign2 sequences have higher translation initiation efficiency.

Designed sequences show improved stability with minimal free energy increase.

Computational TIE metrics validated by large-scale experimental data.

Abstract

Messenger RNA (mRNA) vaccines and therapeutics are emerging as powerful tools against a variety of diseases, including infectious diseases and cancer. The design of mRNA molecules, particularly the untranslated region (UTR) and coding sequence (CDS) is crucial for optimizing translation efficiency and stability. Current design approaches generally focus solely on either the 5' UTR or the CDS, which limits their ability to comprehensively enhance translation efficiency and stability. To address this, we introduce LinearDesign2, an algorithm that enables the co-design of the 5' UTR and CDS. This integrated approach optimizes translation initiation efficiency (TIE), codon adaptation index (CAI), and minimum free energy (MFE) simultaneously. Comparative analyses reveal that sequences designed by LinearDesign2 exhibit significantly higher TIE than those designed by LinearDesign, with only a slight increase in MFE. Further, we validate the accuracy of the computational TIE metric using large-scale parallel translation experimental data. This study highlights the importance of a joint design strategy for the 5' UTR and CDS in optimizing mRNA performance, paving the way for more efficient mRNA vaccines and therapeutics.