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Structure and Dynamics of DNA and RNA Double Helices Obtained from the CCG and GGC Trinucleotide Repeats
journal contribution
posted on 2018-04-04, 00:00 authored by Feng Pan, Viet Hoang Man, Christopher Roland, Celeste SaguiExpansions
of both GGC
and CCG sequences lead to a number of expandable, trinucleotide repeat
(TR) neurodegenerative diseases. Understanding of these diseases involves,
among other things, the structural characterization of the atypical
DNA and RNA secondary structures. We have performed molecular dynamics
simulations of (GCC)n and (GGC)n homoduplexes in order to characterize their conformations,
stability, and dynamics. Each TR has two reading frames, which results
in eight nonequivalent RNA/DNA homoduplexes, characterized by CpG
or GpC steps between the Watson–Crick base pairs. Free energy
maps for the eight homoduplexes indicate that the C-mismatches prefer
anti–anti conformations, while G-mismatches prefer anti–syn
conformations. Comparison between three modifications of the DNA AMBER
force field shows good agreement for the mismatch free energy maps.
The mismatches in DNA-GCC (but not CCG) are extrahelical, forming
an extended e-motif. The mismatched duplexes exhibit characteristic
sequence-dependent step twist, with strong variations in the G-rich
sequences and the e-motif. The distribution of Na+ is highly
localized around the mismatches, especially G-mismatches. In the e-motif,
there is strong Na+ binding by two G(N7) atoms belonging
to the pseudo GpC step created when cytosines are extruded and by
extrahelical cytosines. Finally, we used a novel technique based on
fast melting by means of an infrared laser pulse to classify the relative
stability of the different DNA-CCG and -GGC homoduplexes.
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DNA-CCGnovel techniquestabilityFree energy mapslaser pulseduplexes exhibitDNA-GCCn homoduplexesGGC Trinucleotide Repeats Expansionsneurodegenerative diseasesenergy mapsGpC stepCCG sequencesGCCconformationextrahelical cytosinesNaRNA Double Helices ObtainedDNA AMBER force fieldmismatchG-rich sequencesGpC stepssequence-dependent step twiste-motifGGC homoduplexesTRreading framesdynamics simulationsG-mismatche
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