Intrinsic curvature of DNA : a molecular dynamics study.
DNA intrinsic curvature is, at present, one of the major topics of research concerning
DNA conformation and dynamics because of its implications in phenomena of great
biological relevance including transcription activation and chromatin packaging. DNA
sequences containing runs of adenines residues (A-tracts) are of central importance to this
phenomenon since the length of the A-tracts and their phasing with the helix screw
significantly alter the curvature profile of DNA.
X-ray crystallography of DNA single crystals has provided a wealth of information about
the local, short range conformational features of general-sequence and also A-tractcontaining
DNA oligomers but it lacks the same strength in the analysis of long range
conformational features of DNA. On the other hand, gel-electrophoresis analysis of DNA
has not only uncovered the macroscopic curvature of DNA but it also provides most of
the available data on DNA intrinsic curvature. However, gel electrophoresis can not
identify features of DNA structure at the nucleotide or atomic level.
This work is an attempt of bridging the gap between such techniques by using the
method of molecular dynamics (MD) simulations. MD simulations were performed on
5 A-tract-containing dodecamers, 3 of which have available crystal structures, and on a
51 base-pair DNA fragment from the kinetoplast DNA of Leishmania tarentolae.
The results shows that A-tracts can be strongly curved, contrary to what is expected from
X-ray analysis of DNA single crystals. The detailed analysis of the MD trajectories also
shows that DNA curves towards the major groove. An explanation which demonstrate
the consistence between major groove curvature and uncurving of DNA upon binding
of the antibiotic distamycin is provided. Furthermore, regions of hyperflexibility or
junctions between A-tracts and general-sequence DNA are identified and shown to
modulate DNA intrinsic curvature. The flexibility pattern of the sugar rings can provide
an alternative explanation for the cleavage pattern of A-tract-containing DNA by the
hydroxyl radical. An attempt to predict the curvature of other A-tract-containing DNA
sequences is also presented. It is shown that, in order to realistically represent the
curvature of A-tract-containing DNA, the intrinsic structure of individual A-tracts must
be preserved and not averaged as in the Wedge model. Finally, some computer
experiments are suggested in order to refine our knowledge of DNA conformation and
dynamics using MD simulations before such technique can be routinely used in the
investigation of phenomena of biological and medicinal relevance.