All‐atom polarizable force field for DNA based on the classical drude oscillator model

Abstract

Presented is a first generation atomistic force field for DNA in which electronic polarization is modeled based on the classical Drude oscillator formalism. The DNA model is based on parameters for small molecules representative of nucleic acids, including alkanes, ethers, dimethylphosphate, and the nucleic acid bases and empirical adjustment of key dihedral parameters associated with the phosphodiester backbone, glycosidic linkages and sugar moiety of DNA. Our optimization strategy is based on achieving a compromise between satisfying the properties of the underlying model compounds in the gas phase targeting QM data and reproducing a number of experimental properties of DNA duplexes in the condensed phase. The resulting Drude force field yields stable DNA duplexes on the 100 ns time scale and satisfactorily reproduces (1) the equilibrium between A and B forms of DNA and (2) transitions between the BI and BII sub-states of B form DNA. Consistency with the gas phase QM data for the model compounds is significantly better for the Drude model as compared to the CHARMM36 additive force field, which is suggested to be due to the improved response of the model to changes in the environment associated with the explicit inclusion of polarizability. Analysis of dipole moments associated with the nucleic acid bases shows the Drude model to have significantly larger values than those present in CHARMM36, with the dipoles of individual bases undergoing significant variations during the MD simulations. Additionally, the dipole moment of water was observed to be perturbed in the grooves of DNA.

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

“…The polarizable model also satisfactorily treats the equilibrium between the A, BI and BII conformations of DNA. 102,10 Similar to the polarizable protein model, the dipole moments of the bases are significantly larger than in the additive CHARMM36 model.…”

Triplex intermediates in folding of human telomeric quadruplexes probed by microsecond-scale molecular dynamics simulations

“…Lifetime and stability of the two-tetrad triplex could be affected to a larger extent. Future well-tuned polarizable force fields may provide additional insights into the stability of the G-triplexes [97].…”

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.…”