Distortions in the DNA sequence such as damages or mispairs are specifically
recognized and processed by DNA repair enzymes. A particular challenge for the
enzymatic specificity is the recognition of a wrongly-placed native nucleotide
such as thymine in T:G mispairs. An important step of substrate binding which
is observed in many repair proteins is the flipping of the target base out of
the DNA helix into the enzyme’s active site. In this work we investigate how
much the intrinsic dynamics of mispaired DNA is changed compared to canonical
DNA. Our molecular dynamics simulations of DNA with and without T:G mispairs
show significant differences in the conformation of paired and mispaired DNA.
The wobble pair T:G shows local distortions such as twist, shear and stretch
which deviate from canonical B form values. Moreover, the T:G mispair is found
to be kinetically less stable, exhibiting two states with respect to base
opening: a closed state comparable to the canonical base pairs, and a more
open state, indicating a proneness for base flip. In addition, we observe that
the thymine base in a T:G mispair is significantly more probable to be flipped
than thymine in a T:A pair or cytosine in a C:G pair. Such local deformations
and in particular the existence of a second, more-open state can be speculated
to help the target-site recognition by repair enzymes