Linear Relationship between Deformability and Thermal Stability of 2′-O-Modified RNA Hetero Duplexes

[Image: see text] We describe the relationship between the experimentally determined melting temperatures of 2′-O-modified-RNA/RNA duplexes and their deformability estimated from molecular dynamics simulations. To clarify this relationship, we synthesized several fully modified oligoribonucleotides such as 2′-O-cyanoethyl RNAs and 2′-O-methoxyethyl RNAs and compared the actual melting temperatures of the duplexes with their calculated deformabilities. An increase of the melting temperatures by 2′-O-modifications was found to correlate strongly with an increase of the helical elastic constants in U(14)/A(14), (CU)(7)/(AG)(7), and (GACU)(3)/(AGUC)(3) sequences. Linear regression analyses could be used to estimate the melting temperature with an accuracy of ±2.0 °C in our model case. Although the strong correlation was observed in the same base sequence, the linear regression functions were different from each base sequence. Our results indicated the possibility of predicting the thermal stability of 2′-O-modified duplexes at the computer-aided molecular design stage.