Hydrogen-Bonding Interactions of Methylated Adenine Derivatives

Hydrogen bonding between nucleobases is a crucial noncovalent interaction for the life on Earth. Apart from Watson-Crick binding, Hoogsteen pairing has been found in many structures of nucleic acids. Methylation of nucleic acids (NAs) is a post-replication or post-transcription mechanism that can modulate the structure and function of a NA without changing its sequence. Methylation of adenine at the N-6 position to form m6A is one of the most important and common epigenetic markers. This paper describes an investigation of intermolecular H-bonding interactions of methylated derivatives of adenine with its complementary partner, thymine. Adenine derivatives with (di)methylamino groups in positions 2 or 6 have been prepared and their interactions with a thymine derivative have been studied by NMR spectroscopy and DFT calculations. It has been found that Hoogsteen pairing is preferred for adenine derivatives, which offer two hydrogen-bond sites on both Watson-Crick and Hoogsteen sides of the molecule. Methylation of the N-6 position leads to further stabilization of the Hoogsteen pair.