A 5-nanosecond molecular dynamics trajectory for B-DNA: analysis of structure, motions, and solvation

Abstract

We report the results of four new molecular dynamics (MD) simulations on the DNA duplex of sequence d(CGCGAATTCGCG)2, including explicit consideration of solvent water, and a sufficient number of Na+ counterions to provide electroneutrality to the system. Our simulations are configured particularly to characterize the latest MD models of DNA, and to provide a basis for examining the sensitivity of MD results to the treatment of boundary conditions, electrostatics, initial placement of solvent, and run lengths. The trajectories employ the AMBER 4.1 force field. The simulations use particle mesh Ewald summation for boundary conditions, and range in length from 500 ps to 5.0 ns. Analysis of the results is carried out by means of time series for conformationalm, helicoidal parameters, newly developed indices of DNA axis bending, and groove widths. The results support a dynamically stable model of B-DNA for d(CGCGAATTCGCG)2 over the entire length of the trajectory. The MD results are compared with corresponding crystallographic and NMR studies on the d(CGCGAATTCGCG)2 duplex, and placed in the context of observed behavior of B-DNA by comparisons with the complete crystallographic data base of B-form structures. The calculated distributions of mobile solvent molecules, both water and counterions, are displayed. The calculated solvent structure of the primary solvation shell is compared with the location of ordered solvent positions in the corresponding crystal structure. The results indicate that ordered solvent positions in crystals are roughly twice as structured as bulk water. Detailed analysis of the solvent dynamics reveals evidence of the incorporation of ions in the primary solvation of the minor groove B-form DNA. The idea of localized complexation of otherwise mobile counterions in electronegative pockets in the grooves of DNA helices introduces an additional source of sequence-dependent effects on local conformational, helicoidal, and morphological structure, and may have important implications for understanding the functional energetics and specificity of the interactions of DNA and RNA with regulatory proteins, pharmaceutical agents, and other ligands.

Ultrafast Dynamics in DNA: “Fraying” at the End of the Helix

“…In the computer simulation of Young, et al, the phosphates show the largest increase in motion at the helix terminus. 8 Thus, these simulations suggest that winding/unwinding motions dominate. More detailed analysis of simulations for the type of motion enhanced at the helix terminus and particularly for the rates of these motions would assist in the interpretation of the TRSS results.…”

“…Previous NMR measurements have detected an increased amplitude of motion at the ends of oligonucleotides in the picosecond time range, but could not isolate a time constant for this motion. [4][5][6] X-ray, 3 NMR 4-6 and computer [7][8][9] experiments agree that fraying is largely confined to the last two base-pairs, with most of the motion on the terminal base pair. Two general types of motion can be envisioned, each of which could be detected in a TRSS experiment.…”

Charge transfer in DNA: Hole charge is confined to a single base pair due to solvation effects

“…9 In turn, the weak dependence of i j on j is due to the fact that the distances between charges on the axis of the cylinder and the polar medium are essentially longer than the distance between adjacent pairs, 3.4 Å. This model appears to be rather crude, and it is not supported by the results of moleculardynamics simulations of DNA 18,19 or even by the more extended electrostatic models using a heterogeneous dielectric medium. 2,[6][7][8] As expected, the calculation carried out using 0 = 1 = 2 = 1.0 leads to quite delocalized hole states in ͑GC͒ n .…”

Free Energy Analysis of Protein–DNA Binding: The EcoRI Endonuclease–DNA Complex

“…For the purposes of this study, we proceed according to the following rationale. From the results of Manning theory [38], we expect that condensed monovalent counterions per se neutralize only ∼76% of the DNA charge, a result independently supported by recent large-scale MD simulations [67,68]. Thus, a model with enough fully charged sodium counterions condensed on the DNA to provide local electroneutrality would be unrealistic.…”

“…This necessitates an ad hoc model for counterion release that, no matter how plausible, remains a simplified assumption. The development of dynamical models for counterion behavior around DNA from MD simulations including explicit consideration of all solvent has been reported recently [67,68]. Scaled up to protein DNA complexes, MD holds the promise of providing an ab initio model for counterion release.…”