Comparative Assessment of Different RNA Tetranucleotides from the DFT-D3 and Force Field Perspective

Classical force field (FF) molecular
dynamics (MD) simulations
of RNA tetranucleotides have substantial problems in reproducing conformer
populations indicated by NMR experiments. To provide more information
about the possible sources of errors, we performed quantum mechanical
(QM, TPSS-D3/def2-TZVP) and molecular mechanics (MM, AMBER parm99bsc0+χOL3) calculations of different r­(CCCC), r­(GACC), and r­(UUUU)
conformers obtained from explicit solvent MD simulations. Solvent
effects in the static QM and MM calculations were mimicked using implicit
solvent models (COSMO and Poisson–Boltzmann, respectively).
The comparison of QM and MM geometries and energies revealed that
the two methodologies provide qualitatively consistent results in
most of the cases. Even though we found some differences, these were
insufficient to indicate any systematic corrections of the RNA FF
terms that could improve the performance of classical MD in simulating
tetranucleotides. On the basis of these findings, we inferred that
the overpopulation of intercalated conformers in the MD simulations
of RNA tetramers, which were not observed experimentally, might be
predominantly caused by imbalanced water–solvent and water–water
interactions. Apart from the large-scale QM calculations performed
to assess the performance of the AMBER FF, a representative spectrum
of faster QM methods was tested.