Molecular Dynamics Simulations of the 136 Unique Tetranucleotide Sequences of DNA Oligonucleotides. II. SEQUENCE CONTEXT EFFECTS ON THE DYNAMICAL STRUCTURES OF THE 10 UNIQUE DINUCLEOTIDE STEPS

¹ Wesleyan University
² Scripps Research Institute
³ University of Utah
⁴ Mount Sinai School of Medicine
⁵ Swiss Federal Institute of Technology
⁶ Institut de Biologie Physico-Chimique
⁷ Swiss Federal Inst. of Technology
⁸ Max Delbrueck Center
⁹ Northwestern Univ
¹⁰ University of Cambridge

^* To whom correspondence should be addressed. E-mail: dbeveridge{at}wesleyan.edu.

Submitted on May 25, 2005
Revised on June 19, 2005
Accepted on 16 August 2005

	Abstract

Molecular dynamics (MD) simulations including water and counterions on B-DNA oligomers containing all 136 unique tetranucleotide base pair steps are reported. The objective is to obtain the calculated dynamical structure for at least two copies of each case, and use the results to examine issues with regard to convergence and dynamical stability of MD on DNA, and to 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., 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 ten 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 non-standard conformational substates. The difference in mean of the observed base pair step helicoidal parameter distribution with different flanking sequence sometimes differs by as much as 1 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 base pair neighbors. The results in general provide new insight into MD on DNA and the sequence dependent dynamical structural characteristics of DNA.

Key Words: DNA Structure library, DNA bending, DNA curvature, Molecular dynamics simulation, Sequence directed DNA structure

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