Nucleic Acids Research, Vol 24, Issue 4 775-783, Copyright © 1996 by Oxford University Press
SV Mariappan, AE Garcoa and G Gupta
Anomalous expansion of the DNA triplet (CTG)n causes myotonic dystrophy.
Structural studies have been carried out on (CTG)n repeats in an attempt to
better understand the molecular mechanism of repeat expansion. NMR and gel
electrophoretic studies demonstrate the presence of hairpin structures for
(CTG)5 and (CTG)6 in solution. The monomeric hairpin structure remains
invariant over a wide range of salt concentrations (10-200 mM NaCl), DNA
concentrations (micromolar to millimolar in DNA strand) and pH (6.0-7.5).
The (CTG)n hairpin contains three bases in the loop when n is odd and four
bases when n is even. For both odd and even n the stacking and pairing in
the stem remain the same, i.e, two hydrogen bond T.T pairs stack with the
neighboring G.C pairs. All the nucleotides in (CTG)5 and (CTG)6 adopt
C2'-endo, anti conformations. Full-relaxation matrix analysis has been
performed to derive the NOE distance constraints from NOESY experiments at
seven different mixing times (25, 50, 75, 100, 125, 200 and 500 ms). NOESY-
derived distance constraints were subsequently used in restrained molecular
dynamics simulations to obtain a family of structures consistent with the
NMR data. The theoretical order parameters are computed for
H5-H6(cytosines) and H2'-H2" dipolar correlations for both (CTG)5 and
(CTG)6 by employing the Lipari-Szabo formalism. Experimental data show that
the cytosine in the loop of the (CTG)5 hairpin is slightly more flexible
than those in the stem. The cytosine in the loop of the (CTG)6 hairpin is
extremely flexible, implying that the dynamics of the four base loop is
intrinsically different from that of the three base loop.
ARTICLES
Structure and dynamics of the DNA hairpins formed by tandemly repeated CTG triplets associated with myotonic dystrophy
Theoretical Biology and Biophysics, Los Alamos National Laboratory, Los Alamos, NM 87545, USA.
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