RNA Folding Nearest Neighbor Parameters Including the Modification 1-Methyl-Pseudouridine

Area of Science:

• Biochemistry
• Molecular Biology
• Computational Biology

Background:

• Nearest neighbor analysis is crucial for predicting RNA folding stability.
• 1-methyl-pseudouridine is a key modification in mRNA vaccines, but its impact on RNA folding was not well understood.

Purpose of the Study:

• To develop and validate new nearest neighbor parameters for RNA folding that include 1-methyl-pseudouridine.
• To improve the accuracy of predicting RNA secondary structures with this modified nucleobase.

Main Methods:

• Derived new nearest neighbor parameters using 208 optical melting experiments.
• Tested the parameters against an additional 16 optical melting experiments.
• Incorporated parameters for 1-methyl-pseudouridine-adenine and 1-methyl-pseudouridine-guanine base pairs, as well as loop stability estimations.

Main Results:

• 1-methyl-pseudouridine substitution generally stabilizes RNA folding, with sequence-dependent effects.
• The new parameters significantly improved the estimation of tRNA folding ensembles containing 1-methyl-pseudouridine.
• The developed parameters are integrated into the RNAstructure software.

Conclusions:

• The new nearest neighbor parameters enable accurate modeling of RNA secondary structures with 1-methyl-pseudouridine.
• These parameters are vital for understanding and designing mRNA therapeutics and analyzing natural RNA sequences.