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* Chemistry Department and Molecular Biophysics Program, Wesleyan University, Middletown, Connecticut 06459; Department of Molecular Biology, TPC15, The Scripps Research Institute, La Jolla, California 92037; Departments of Medicinal Chemistry and of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, Utah 84112-5820; Laboratoire de Biochimie Theorique, Institut de Biologie PhysicoChimique, Paris 75005, France; ¶ Physiology and Biophysics, Mount Sinai School of Medicine, New York, New York 10029; || Institute of Mathematics B, Swiss Federal Institute of Technology, CH 1015 Lausanne, Switzerland; and ** Theoretical Biophysics Group, Max Delbrück Center, D-13122 Berlin, Germany
Correspondence: Address reprint requests to David L. Beveridge, E-mail: dbeveridge{at}wesleyan.edu.
Molecular dynamics (MD) simulations including water and counterions on B-DNA oligomers containing all 136 unique tetranucleotide basepair steps are reported. The objective is to obtain the calculated dynamical structure for at least two copies of each case, use the results to examine issues with regard to convergence and dynamical stability of MD on DNA, and determine the significance of sequence context effects on all unique dinucleotide steps. This information is essential to understand sequence effects on DNA structure and has implications on diverse problems in the structural biology of DNA. Calculations were carried out on the 136 cases embedded in 39 DNA oligomers with repeating tetranucleotide sequences, capped on both ends by GC pairs and each having a total length of 15 nucleotide pairs. All simulations were carried out using a well-defined state-of-the-art MD protocol, the AMBER suite of programs, and the parm94 force field. In a previous article (Beveridge et al. 2004. Biophysical Journal. 87:3799–3813), the research design, details of the simulation protocol, and informatics issues were described. Preliminary results from 15 ns MD trajectories were presented for the d(CpG) step in all 10 unique sequence contexts. The results indicated the sequence context effects to be small for this step, but revealed that MD on DNA at this length of trajectory is subject to surprisingly persistent cooperative transitions of the sugar-phosphate backbone torsion angles 
and 
. In this article, we report detailed analysis of the entire trajectory database and occurrence of various conformational substates and its impact on studies of context effects. The analysis reveals a possible direct correspondence between the sequence-dependent dynamical tendencies of DNA structure and the tendency to undergo transitions that "trap" them in nonstandard conformational substates. The difference in mean of the observed basepair step helicoidal parameter distribution with different flanking sequence sometimes differs by as much as one standard deviation, indicating that the extent of sequence effects could be significant. The observations reveal that the impact of a flexible dinucleotide such as CpG could extend beyond the immediate basepair neighbors. The results in general provide new insight into MD on DNA and the sequence-dependent dynamical structural characteristics of DNA.
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