Oligonucleotide structure is dictated by a balance among hydrophobic base-stacking interactions, hydrogen bonding, solvation, electronic repulsion in the anionic backbone, and favorable backbone-cation interactions. As such, the dynamics of DNA and RNA are sensitive to accurate force-field treatment of each of these forces. Here, we present the development of the most recent version of a polarizable force field for DNA and RNA based on the classical Drude oscillator model, called Drude-2017. The force field has been calibrated against high-level quantum mechanical base stacking, hydrogen bonding, water interaction, and ion interaction calculations and has been validated against duplex A-, B-, and Z-DNA and a range of secondary and tertiary RNA folds, some in the presence of the strongly polarizing divalent magnesium ion. Using microsecond molecular dynamics simulations, we show that Drude-2017 is capable of reproducing experimental observables for these nucleic acids in solution, including small-angle X-ray scattering profiles of B-DNA, the solvent-dependent A-B transition of DNA, and stability of Z-DNA structures in the crystalline state. RNA simulations demonstrate that duplex A-RNA is stable and that stem-loop structures preserve critical interactions, notably in the UUCG motif. Expanding upon these findings, we have applied Drude-2017 to noncanonical DNA and RNA folds known as G-quadruplexes (GQs), which are characterized by planar tetrads of Hoogsteen hydrogen-bonded guanine bases that coordinate potassium cations. The inclusion of electronic polarization via the Drude model is essential for retention of the ions and stability of the tetrad core. Notably, the nucleobases in different motifs (GQ tetrad core, unpaired RNA loops, duplexes, etc.) have different electronic structures, as quantified by molecular dipole moments. These findings suggest that nucleobases are extremely sensitive to solvation and noncanonical interactions, therefore emphasizing the importance of electronic polarization in atomistic simulations of nucleic acids.

Development of the drude polarizable force field for DNA and RNA and application to investigations of nucleic acid structure and dynamics

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

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