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

Molecular dynamics (MD) simulations including water and counterions are rep orted on five examples of A-tract DNA oligonucleotide dodecamer duplexes fo r which crystal structures are available, the homopolymeric duplex sequence s 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 sequenc e. These results, combined with previously reported MDs on 25-mer and 30-me r oligonucleotides on sequences with phased A-tracts carried out under a si milar simulation protocol, are used to examine salient issues in the struct ural chemistry of ApA steps and A-tract induced axis bending. MD modeling s ucessfully describes the distinctive B' structure of A-tracts in solution a s essentially straight (wedge angles of <1), more rigid than generic B-form DNA, with slight base-pair inclination, high propeller twist and a minor g roove narrowing 5' to 3. The MD structures in solution agree closely with c orresponding crystal structures, supporting the idea that crystal structure s provide a good model for A-tract DNA structure in solution. From the coll ective MD results, bending and flexibility are calculated by step. Pyrimidi ne-purine steps are predicted to be most intrinsically bent and also most b endable, i.e. susceptible to bending. Pyrimidine-pyrimidine (similar to pur ine-purine) and purine-pyrimidine steps Shaw less intrinsic deformation and deformability. The MD calculated flexibility correlates well with the prot ein-induced bendability derived independently from the protein DNA crystal structures. The MD results indicate that bending and flexibility of base-pa ir steps in DNA are highly correlated, i.e. steps that exhibit the most int rinsic deformation from B-form DNA turn are also the most dynamically defor mable. The MD description of A-tract-induced axis bending shows most consis tency with the non A-tract, general-sequence model, in which the sequence c urvature 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 opposit e 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 i nferred for DNA sequences from gel retardation and cyclization experiments. (C) 2001 Academic Press.