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.

A new procedure for the analysis of the structure and molecular dynamics of duplex DNA is introduced, in which comprehensive visualization of results and pattern recognition is greatly facilitated. The method involves determining the values of the conformational and helicoidal parameters for each structure entering the analysis using the method "Curves" developed by Lavery and Sklenar, J. Biomol. Str. Dyn. 6, 63 (1988), followed by a novel computer graphic display of the results. The graphic display is organized systematically using conformation wheels, or "dials", for each IUPAC torsional parameter and "windows" on the range of values assumed by the linear and angular helicoidal parameters, and is presented in a form isomorphous with the structure per se. The complete time evolution of the conformational and helicoidal parameters of a DNA double helix can then be depicted in a set of six composite figures. Dynamical aspects of helix bending are also subsumed in this analysis. The procedure is illustrated with an analysis of the structures of canonical A and B forms of DNA and the 300 degrees K native dodecamer duplex d(CGCGAATTCGCG). The "dials and windows" are then used for a comprehensive analysis of 30 psec of molecular dynamics on the dodecamer in the vicinity of a canonical B-DNA energy minimum. This involves presentation of the time evolution of 206 conformational and 230 helicoidal parameters for the dodecamer. A number of interesting structural features can be recognized in the analysis, including crankshaft motions, BI - BII transitions, sugar repuckerings, and a description of spontaneous helix bending at what corresponds to the 1 degrees and 2 degrees "hinge points" indicated in the crystal structure. Our approach is expected to be directly useful for critical analysis of the effects of various assumptions about force field parameters, hydration and electrostatic effects and thus contribute to the development of reliable simulation protocols for nucleic acid systems. Extension of the method to present differential changes in conformational and helicoidal parameters is expected to be valuable for the analysis of structural and molecular dynamics studies of the reorganization and adaptation of DNA on complexation with various drugs and regulatory proteins.

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Sequence-dependent bending of the helical axes in 112 oligonucleotide duplex crystal structures resident in the Nucleic Acid Database have been analyzed and compared with the use of bending dials, a computer graphics tool. Our analysis includes structures of both A and B forms of DNA and considers both uncomplexed forms of the double helix as well as those bound to drugs and proteins. The patterns in bending preferences in the crystal structures are analyzed by base pair steps, and emerging trends are noted. Analysis of the 66 B-form structures in the Nucleic Acid Database indicates that uniform trends within all pyrimidine-purine and purine-pyrimidine steps are not necessarily observed but are found particularly at CG and GC steps of dodecamers. The results support the idea that AA steps are relatively straight and that larger roll bends occur at or near the junctions of these A-tracts with their flanking sequences. The data on 16 available crystal structures of protein-DNA complexes indicate that the majority of the DNA bends induced via protein binding are sharp localized kinks. The analysis of the 30 available A-form DNA structures indicates that these structures are also bent and show a definitive preference for bending into the deep major groove over the shallow minor groove.

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