Methyl group configuration on acyclic threoninol nucleic acids ( a TNAs) impacts supramolecular properties.

We have synthesized acyclic allo -threoninol nucleic acids ( allo-a TNAs), artificial xeno-nucleic acids (XNAs) that are diastereomers of acyclic threoninol nucleic acids ( a TNAs), and have investigated their supramolecular properties. The allo-a TNAs formed homo-duplexes in an antiparallel manner but with lower thermal stability than DNA, whereas a TNAs formed extremely stable homo-duplexes. The allo-a TNAs formed duplexes with complementary a TNAs and serinol nucleic acid (SNA). The affinities of L- allo-a TNA were the highest for L- a TNA and the lowest for D- a TNA, with SNA being intermediate. The affinities of D- allo-a TNA were the reverse. Circular dichroism measurements revealed that L- and D- allo-a TNAs had weak right-handed and left-handed helicities, respectively. The weak helicity of allo-a TNAs likely explains the poor chiral discrimination of these XNAs, which is in contrast to a TNAs that have strong helical orthogonality. Energy-minimized structures of L- allo-a TNA/RNA and L- allo-a TNA/L- allo-a TNA indicated that the methyl group on the allo-a TNA strand is unfavourable for duplex formation. In contrast, the methyl group on L- a TNA likely stabilizes the duplex structure via hydrophobic effects and van der Waals interactions. Thus, the configuration of the methyl group on the XNA scaffold had an unexpectedly large impact on the hybridization ability and structure.