Structure and Dynamics of DNA and RNA Double Helices Formed by d(CTG), d(GTC), r(CUG), and r(GUC) Trinucleotide Repeats and Associated DNA–RNA Hybrids

Myotonic dystrophy type 1 is the most frequent form of muscular dystrophy in adults caused by an abnormal expansion of the CTG trinucleotide. Both the expanded DNA and the expanded CUG RNA transcript can fold into hairpins. Co-transcriptional formation of stable RNA·DNA hybrids can also enhance the instability of repeat tracts. We performed molecular dynamics simulations of homoduplexes associated with the disease, d(CTG)nand r(CUG)n, and their corresponding r(CAG)n:d(CTG)nand r(CUG)n:d(CAG)nhybrids that can form under bidirectional transcription and of non-pathological d(GTC)nand d(GUC)nhomoduplexes. We characterized their conformations, stability, and dynamics and found that the U·U and T·T mismatches are dynamic, favoring anti–anti conformations inside the helical core, followed by anti–syn and syn–syn conformations. For DNA, the secondary minima in the non-expanding d(GTC)nhelices are deeper, wider, and longer-lived than those in d(CTG)n, which constitutes another biophysical factor further differentiating the expanding and non-expanding sequences. The hybrid helices are closer to A-RNA, with the A-T and A-U pairs forming two stable Watson–Crick hydrogen bonds. The neutralizing ion distribution around the non-canonical pairs is also described.