Structural and thermodynamic consequences of base pairs containing pseudouridine and N1-methylpseudouridine in RNA duplexes
Pseudouridine ({Psi}) is one of the most common post-transcriptional modifications in RNA and has been known to play significant roles in several crucial biological processes. The N1-methyl derivative of pseudouridine i.e N1-methylpseudouridine has also been reported to be important for the stability and function of RNA. Several studies suggest the importance of pseudouridine and N1-methylpseudouridine in mRNA therapeutics. The critical contribution of pseudouridine, especially that of its N1-methyl derivative in the efficiency of the COVID-19 mRNA vaccines, suggests the requirement to better understand the role of these modifications in the structure, stability and function of RNA. In the present study, we have investigated the consequences of the presence of these modifications in the stability of RNA duplex structures by analyzing different structural properties, hydration characteristics and energetics of these duplexes. We have previously studied the structural and thermodynamic properties of RNA duplexes with an internal {Psi}-A pair and reported the stabilizing effect of {Psi} over U (Deb, I. et al. Sci Rep 9, 16278 (2019)). Here, we have extended our work to understand the properties of RNA duplexes with an internal m1{Psi}-A pair and also theoretically demonstrate the effect of substituting internal U-G, U-U and U-C mismatches with the {Psi}-G, {Psi}-U and {Psi}-C mismatches and also with the m1{Psi}-G, m1{Psi}-U and m1{Psi}-C mismatches respectively, within dsRNA. Our results indicate the context-dependent stabilization of base stacking interactions by N1-methylpseudouridine compared to uridine and pseudouridine, presumably resulting from the increased molecular polarizability due to the presence of the methyl group.