Computational evaluation of the stability of 2′-O-methyl-RNA/RNA duplexes incorporating 3-deazaguanine derivatives by ab initio calculations and a molecular dynamics simulation

We evaluated the intrinsic interactions of guanine (G), 3-deazaguanine (c3G), and 2-N-acetyl-3-deazaguanine (a2c3G) with neighboring bases in the 2′-O-methyl-RNA/RNA duplex, 5′-(C1G2G3C4X5A6G7G8A9G10)-3′/3′-r(G20C19C18G17C16U15C14C13U12C11)-5′, where X = G, c3G, or a2c3G. We calculated the energies using the subsystems that were derived from the averaged structure of the molecular dynamics (MD) trajectories of the duplexes by removing the sugar and phosphate moieties. The total energies calculated in vacuo revealed that the stability order was roughly a2c3G-C >> G-C > c3G-C, which was not perfectly matched with the experimentally determined stability order of G-C > a2c3G-C >> c3G-C probably due to lack of information on the solvent effects. The stacking interactions of c3G and its neighboring bases were smaller than those of G probably because of the larger dipole moment of c3G, whereas the stacking interaction of a2c3G was in most cases larger than those of G and c3G due to the increased overlapping area of the acetyl group and the smaller dipole moment. The data also gave an insight into the mechanism of duplex stabilization of a2c3G compared with c3G. In order to estimate the solvent effects, we also conducted ab initio calculations with some solute models.