Influence of the Number, Nature and Position of Methyl Posttranscriptional Modifications on Nucleobase Stacking in RNA

Abstract

DFT calculations are employed to quantify the influence of the presence, number, nature, and position of posttranscriptional methylation on stacking strength of RNA bases. We carry out detailed potential energy scans of the variation in stacking energies with characteristic geometrical parameters in three categories of forty stacked dimers – canonical base homodimers (N||N), methylated base homodimers (mN||mN) and heterodimers of canonical bases and methylated counterparts (N||mN). Our analysis reveals that neutral methylation invariably enhances the stacking of bases. Further, N||mN stacking is stronger than mN||mN stacking and charged N||mN exhibit strongest stacking among all dimers. This indicates that methylations greatly enhance stacking when dispersed in RNA sequences containing identical bases. Comparison of stacks involving singly‐ and doubly‐methylated purines reveal that incremental methylation enhances the stacking in neutral dimers. Although methylation at the carbon position of neutral pyrimidine dimers greatly enhances the stacking, methylation on the 5‐membered ring imparts better stacking compared to methylation on the 6‐membered ring in adenine dimers. However, methylation at the ring nitrogen (N1) provides better stacking than the amino group (N2) in guanine dimers. Our results thus highlight subtle structural effects of methylation on RNA base stacking and will enhance our understanding of the physicochemical principles of RNA structure and dynamics.

Structural Properties of Hachimoji Nucleic Acids and Their Building Blocks: Comparison of Genetic Systems with Four, Six and Eight Alphabets

“…The optimized pyrimidines (C, T, U, S, rS, and Z) were then stacked by aligning the geometrical centers of their six-membered heterocyclic rings, while purines (B, P, A, and G) were stacked by aligning the centers of the ninemembered rings formed by including all the purine skeletal atoms. [16,42,44,46,50] In agreement with previous studies on stacking between canonical and noncanonical bases, [46,51,52] as well as between canonical bases and aromatic amino acids, [53,54] the BSSEcorrected interaction energy profiles of all possible stacked dimeric combinations (Figure S14) were analysed at the B3LYP-D3BJ/6-311 + G(2df,p) level as a function of four geometrical parameters. These include the vertical separation between the stacked monomers (R 1 ), the angle of rotation about an axis passing through the centers of rings of the monomers (α), and the relative horizontal shift (R 2 ) of the monomers in X-and Y- ChemPhysChem directions (Figure 5).…”

“…[45] Partial atomic charges for evaluating the electrostatic component of the force field were obtained using B3LYP-D3BJ/6-31G(d,p), which was selected based on its success in modeling the properties of similar nucleic-acid systems. [16,42,46] More than 1000 conformers were obtained from the conformational search on each nucleoside. From these, ten lowest-energy conformers were selected for full optimization using B3LYP-D3BJ/6-31G(d,p).…”

“…In analogy with previous studies, [42,44,46,50] the relative monomer orientation for the R 1 scan was chosen by aligning the GÀ H bonds of the stacked monomers, where G represents the atom of the base which glycosidic bonds with the sugar. This corresponds to the 0°of the angle of rotation (α).…”

Molecular Dynamics Simulations of the Aptamer Domain of Guanidinium Ion Binding Riboswitch ykkC-III: Structural Insights into the Discrimination of Cognate and Alternate Ligands

“…However, for nucleotides interacting through the Hoogsteen or Watson–Crick edge, the sugar-phosphate backbone was removed and the dangling glycosidic bond was saturated with a hydrogen atom. Optimizations were then performed on these models at the B3LYP-D3BJ/6-31G­(d,p) level. , This method was selected in analogy with previous studies on nucleic acid fragments. ,− The choice of this method is further justified based on previous CCSD­(T)/CBS benchmarks, which suggest reasonable performance of the dispersion-corrected B3LYP functional with a Pople’s triple-zeta quality basis set . The basis set superposition error corrected binding strength of each of these models was estimated at the B3LYP-D3BJ/6-311 + G­(2df,p) level, following previous studies. , All quantum chemical calculations were performed using Gaussian 09…”

Role of Main RNA Methylation in Hepatocellular Carcinoma: N6-Methyladenosine, 5-Methylcytosine, and N1-Methyladenosine

“…RNA methylation is commonly regarded as posttranscriptional modification with multiple forms ( Chen et al, 2019 ; Kagra et al, 2021 ). Although epigenetic modification of RNA has been documented over several decades ( Cohn, 1960 ; Dubin and Taylor, 1975 ; Perry et al, 1975 ), our understanding of its biological functions is still limited.…”