Molecular dynamics simulations of B '-DNA: sequence effects on A-tract-induced bending and flexibility.

Molecular dynamics (MD) simulations including water and counterions are reported on five examples of A-tract DNA oligonucleotide dodecamer duplexes for which crystal structures are available, the homopolymeric duplex sequences poly(dA) and poly(dG), and two related sequences that serve as controls. MD was performed using the AMBER suite of programs for 3 ns on each sequence. These results, combined with previously reported MDs on 25-mer and 30-mer oligonucleotides on sequences with phased A-tracts carried out under a similar simulation protocol, are used to examine salient issues in the structural chemistry of ApA steps and A-tract induced axis bending. MD modeling successfully describes the distinctive B' structure of A-tracts in solution as essentially straight (wedge angles of <1 degrees ), more rigid than generic B-form DNA, with slight base-pair inclination, high propeller twist and a minor groove narrowing 5' to 3'. The MD structures in solution agree closely with corresponding crystal structures, supporting the idea that crystal structures provide a good model for A-tract DNA structure in solution. From the collective MD results, bending and flexibility are calculated by step. Pyrimidine-purine steps are predicted to be most intrinsically bent and also most bendable, i.e. susceptible to bending. Pyrimidine-pyrimidine ( approximately purine-purine) and purine-pyrimidine steps show less intrinsic deformation and deformability. The MD calculated flexibility correlates well with the protein-induced bendability derived independently from the protein DNA crystal structures. The MD results indicate that bending and flexibility of base-pair steps in DNA are highly correlated, i.e. steps that exhibit the most intrinsic deformation from B-form DNA turn are also the most dynamically deformable. The MD description of A-tract-induced axis bending shows most consistency with the non A-tract, general-sequence model, in which the sequence curvature originates primarily in base-pair roll towards the major groove in non-A-tract regions of the sequence, particularly pyrimidine-purine steps. The direction of curvature is towards the minor groove viewed from opposite the A-tracts, but the A-tracts per se exhibit only minor deformation. The MD results are found to be consistent with the directionality of bending inferred for DNA sequences from gel retardation and cyclization experiments.