Balancing the Interactions of Ions, Water, and DNA in the Drude Polarizable Force Field

Abstract

Recently we presented a first-generation all-atom Drude polarizable force field for DNA based on the classical Drude oscillator model, focusing on optimization of key dihedral angles followed by extensive validation of the force field parameters. Presently, we describe the procedure for balancing the electrostatic interactions between ions, water, and DNA as required for development of the Drude force field for DNA. The proper balance of these interactions is shown to impact DNA stability and subtler conformational properties, including the conformational equilibrium between the BI and BII states, and the A and B forms of DNA. The parametrization efforts were simultaneously guided by gas-phase quantum mechanics (QM) data on small model compounds and condensed-phase experimental data on the hydration and osmotic properties of biologically relevant ions and their solutions, as well as theoretical predictions for ionic distribution around DNA oligomer. In addition, fine-tuning of the internal base parameters was performed to obtain the final DNA model. Notably, the Drude model is shown to more accurately reproduce counterion condensation theory predictions of DNA charge neutralization by the condensed ions as compared to the CHARMM36 additive DNA force field, indicating an improved physical description of the forces dictating the ionic solvation of DNA due to the explicit treatment of electronic polarizability. In combination with the polarizable DNA force field, the availability of Drude polarizable parameters for proteins, lipids, and carbohydrates will allow for simulation studies of heterogeneous biological systems.

CHARMM additive and polarizable force fields for biophysics and computer-aided drug design

“…Refinement of that model required significant adjustments of the phosphodiester backbone and glycosidic bond dihedral parameters, of base-sodium interactions and of selected electrostatic parameters in the model. 101 The resulting DNA force field yields RMSDs similar to the CHARMM36 force field for a number duplexes on the 100 ns timescale, improved agreement in NMR order parameters for the EcoRI dodecamer, and improved agreement with counterion condensation theory with respect to charge neutralization by NaCl. The polarizable model also satisfactorily treats the equilibrium between the A, BI and BII conformations of DNA.…”

Extracting water and ion distributions from solution x-ray scattering experiments

“…There are also some studies in the literature reporting a misbalance between solute-water and solute-solute interactions, which is probably relevant to the situation here. [54][55][56][57][58] Our current ongoing work suggests that the distribution of partial atomic charges within the phosphate group needs to be adjusted to calibrate the DNA-water interaction. A full analysis of those errors is beyond the scope of this paper and will be presented elsewhere.…”

Close encounters with DNA

“…Next-generation force fields may include a dynamic description of molecular properties such as polarizability [100, 101]. For example, a polarizable CHARMM force field based on a classical Drude oscillator model with a complete description of DNA, water, and ions was published recently [102, 103]. This model was optimized using several different levels of computations: quantum calculations for base-cation interactions and backbone torsions; thermodynamic osmotic pressure calculation for cation-phosphate interactions; hydration free energy calculation for DNA-water interactions.…”