Conformational preferences of inosine and its methyl derivatives: Comparison of the AMBER derived force field parameters and reparameterization of the glycosidic torsion parameters

Abstract

Abstract Inosine is one of the most abundant post-transcriptionally modified ribonucleosides which is known to play a major role in several important biological processes and is of great therapeutic importance. The growing importance of this modified ribonucleoside in therapeutics suggests the requirement of further theoretical studies involving inosine and its derivatives and ensuring the accuracy of their force field parameters is crucial for such theoretical studies to be reliable. The present study reports the validation of the AMBER derived force field parameter sets for inosine as well as examination of the transferability of the available revised sets of glycosidic and gamma torsion parameters corresponding to the respective canonical nucleosides based on detailed comparison of different conformational features from replica exchange molecular dynamics. We also report newly developed sets of partial atomic charges and glycosidic torsion parameters (𝛘KOL0) for inosine and its methyl derivatives. These parameters, in combination with the AMBER FF99 parameters (Cheatham, T. E., III; Cieplak, P.; Kollman, P. A. J. Biomol. Struct. Dyn. 1999, 16, 845 − 862; Aduri, R.; Psciuk, B. T.; Saro, P.; Taniga, H.; Schlegel, H. B.; SantaLucia, J. J. Chem. Theory Comput. 2007, 3, 1464 − 1475), and the recommended bsc0 correction for the gamma torsion (Pérez, A.; Marchán, I.; Svozil, D.; Sponer, J.; Cheatham, T. E.; Laughton, C. A.; Orozco, M. Biophys. J. 2007, 3817 − 3829.), reproduced the conformational properties of inosine and its 1-methyl derivative in agreement with experimental (NMR) data. In this study, we have also predicted the conformational preferences for the other two methyl derivatives of inosine, i.e., 2’-O-methylinosine and 1,2’-O-dimethylinosine using the revised sets of glycosidic torsion parameters.