Throughout our investigations, we have observed that neither pure DFT nor pure MM methods we tested could reproduce the conformational behavior of non-natural nucleosides in solution.
While DFT accounts for hyperconjugation effects, solvent effects such as H-bonds in water can only be reproduced by MM techniques (explicit solvent molecules).
A hybrid QM/MM method was the solution to investigate the conformational preferences of a variety of nucleosides and modified monosaccharides.
This method yielded reliable structures that closely matched the crystal structures for the modified monosaccharides, as well as North/South ratios close to experimental ones for both the monosaccharides and nucleosides.
Moreover, our method provides key insights into the role of the substituents on the sugar ring of nucleosides and the finely tuned control of sugar puckering by hyperconjugation effects and intramolecular H-bonding.
However, the method we describe here also has limitations, such as improper sulfur parametrization and underestimated strengths of H-bonds.
Nonetheless, we believe that if the system of interest is a non-natural nucleoside,one can obtain reliable structures and North/South ratios (if only for a qualitative description of one’s system before attempting synthesis) by using a QM/MM approach involving the SCC-DFTB method.
Keywords : · Umbrella Sampling Simulations · Natural Bond Orbital Analysis · H-bonds · Hyperconjugation · Sugar Puckering
Key people involved in the project : Mihai Burai Patrascu (PhD '20, PDF)
Key publications related to the project : here