Molecular dynamics simulations of the 136 unique tetranucleotide sequences of DNA oligonucleotides. Sequence context effects on the dynamical structures of the 10 unique dinucleotide steps

Saturday, May 7, 2005 - 9:00am - 9:45am
EE/CS 3-180
David Beveridge (Wesleyan University)
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 outstanding issues with regard to methods and protocols in MD on DNA, convergence and dynamical stability, and to determine the significance of sequence context effects on all unique dinucleotide steps. This information is essential to understanding 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 imbedded 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 (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 a and g. Here, we report detailed analysis of the entire trajectory database. In particular, we present results on the occurrence of various conformational substates in the light of related experimental observation and discuss their impact on studies of context effects in DNA. At the tetranucleotide level, we observe that in many cases the difference in mean of the individual base pair step helicoidal parameter distributions with different flanking sequence differs by as much as 1 standard deviation, implying that the sequence effects could be significant. We present a novel analysis based on 2D-RMS data for studying the differences in structure and flexibility and employ it to analyze the flexibility of the dinucleotide steps and the effect of the base pair flanking the dinucleotide in the tetra-nucleotide sequences. We observe that the presence of pyrimidine-purine (YpR) steps, esp. the CpG and CpA steps greatly increases the flexibility of DNA while the purine-purine step (YpY/RpR) has a rigidifying effect. The neighboring base pair steps act cooperatively in such a way that the flexible steps tend to dominate the nature of the DNA sequence, there by leading to greater flexibility of the YpY steps in the neighborhood of YpR steps. Further, we observe that the effect of flexible YpR steps extends beyond its place as the first neighbor.