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.

Condensation of monovalent counterions around DNA influences polymer properties of the DNA chain. For example, the Na(+) ions show markedly stronger propensity to induce multiple DNA chains to assemble into compact structures compared with the K(+) ions. To investigate the similarities and differences in the sodium and potassium ion condensation around DNA, we carried out a number of extensive all-atom molecular dynamics simulations of a DNA oligomer consisting of 16 base pairs, [d(CGAGGTTTAAACCTCG)](2), in explicit water. We found that the Na(+) ions penetrate the DNA interior and condense around the DNA exterior to a significantly larger degree compared with the K(+) ions. We have provided a microscopic explanation for the larger Na(+) affinity toward DNA that is based on a combination of steric, electrostatic, and hydration effects. Unexpectedly, we found that the Cl(-) co-ions provide more efficient electrostatic screening for the K(+) ions than for the Na(+) ions, contributing to the larger Na(+) condensation around DNA. To examine the importance of the discrete nature of water and ions, we also computed the counterion distributions from the mean-field electrostatic theory, demonstrating significant disagreements with the all-atom simulations. Prior experimental results on the relative extent of the Na(+) and K(+) condensation around DNA were somewhat contradictory. Recent DNA compaction experiments may be interpreted to suggest stronger Na(+) condensation around DNA compared to K(+), which is consistent with our simulations. We also provide a simple interpretation for the experimentally observed increase in DNA electrophoretic mobility in the alkali metal series, Li(+) < Na(+) < K(+) < Rb(+). We compare the DNA segment conformational preferences in various buffers with the proposed NMR models.

Coarse-grained (CG) modeling approaches are widely used to simulate many important biological processes involving DNA, including chromatin folding and genomic packaging. The bending propensity of a semiflexible DNA molecule critically influences these processes. However, existing CG DNA models do not retain a sufficient fidelity of the important local chain motions, whose propagation at larger length scales would generate correct DNA persistent lengths, in particular when the solution's ionic strength is widely varied. Here we report on a development of an accurate CG model for the double-stranded DNA chain, with explicit treatment of mobile ions, derived systematically from all-atom molecular dynamics simulations. Our model generates complex local motions of the DNA chain, similar to fully atomistic dynamics, leading also to a quantitative agreement of our simulation results with the experimental data on the dependence of the DNA persistence length on the solution ionic strength. We also predict a structural transition in a torsionally stressed DNA nanocircle as the buffer ionic strength is increased beyond a threshold value. T o successfully model many biological processes involving DNA, atomistic or coarse-grained (CG) DNA force fields should reproduce the bending rigidity of a semiflexible DNA chain, which is a large-scale polymer property of critical significance (1, 2). In particular, the response of the DNA persistence length to the change in the surrounding ionic environment is of major biological importance. For example, even a slight change in the persistence length of a linker DNA segment connecting adjacent nucleosomes in the chromatin fiber, induced by the variation of the ionic strength of the solution, may result in significant conformational changes of a chromatin in a compact state (3). Current structure-based DNA models (4, 5) do not generate DNA persistence length values that are fully consistent with those measured experimentally in a wide range of ionic concentrations, c ∼ ½0.1-100 mM (6-8). These and other DNA models differ in resolution in terms of representing both the DNA structure and also the surrounding ionic environment.The discrete nature of mobile ions and spatial correlations among them may significantly affect structure, dynamics, and the electrostatic atmosphere of many biomolecules, such as DNA and RNA (9-15). Thus, explicit inclusion of the monovalent mobile ions into the CG model of DNA is desirable from the physical standpoint. Another vital aspect of DNA modeling is a choice of the parametrization protocol. Many prior one-bead DNA models were based on use of the phenomenological wormlike chain Hamiltonian (16,17). In more detailed structure-based models, parameters are often derived by combining the statistical information from the available crystal structures with some specific experimental data (4). However, this parametrization approach, which is focused on matching a small number of integral experimental characteristics (for example, the melting temperature or free ener...

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.

In the present study we report on interactions of and competition between monovalent ions for two DNA sequences in MD simulations. Efforts included the development and validation of parameters for interactions among the first-group monovalent cations, Li+, Na+, K+ and Rb+, and DNA in the Drude polarizable and additive CHARMM36 force fields (FF). The optimization process targeted gas-phase QM interaction energies of various model compounds with ions and osmotic pressures of bulk electrolyte solutions of chemically relevant ions. The optimized ionic parameters are validated against counterion condensation theory and buffer exchange-atomic emission spectroscopy measurements providing quantitative data on the competitive association of different monovalent ions with DNA. Comparison between experimental and MD simulation results demonstrates that, compared to the additive CHARMM36 model, the Drude FF provides an improved description of the general features of the ionic atmosphere around DNA and leads to closer agreement with experiment on the ionic competition within the ion atmosphere. Results indicate the importance of extended simulation systems on the order of 25 Å beyond the DNA surface to obtain proper convergence of ion distributions.