Molecular Modeling on Duplexes with Threose-Based TNA and TPhoNA Reveals Structural Basis for Different Hybridization Affinity toward Complementary Natural Nucleic Acids

Synthetic nucleic acids, also defined as xenobiotic nucleic acids (XNAs), opened an avenue to address the limitations of nucleic acid therapeutics and the development of alternative carriers for genetic information in biotechnological applications. Two related XNA systems of high interest are the α-l-threose nucleic acid (TNA) and (3'-2') phosphonomethyl threosyl nucleic acid (tPhoNA), where TNAs show potential in antisense applications, whereas tPhoNAs are investigated for their predisposition toward orthogonal genetic systems. We present predictions on helical models of TNA and tPhoNA chemistry in homoduplexes and in complex with native ribose chemistries. A stretched right-handed helical structure with a sugar puckering preference for the _4<i>'</i>^3<i>'</i><i>T</i> (<i>C</i>3<i>'</i>- <i>endo</i>/<i>C</i>4<i>'</i>- <i>exo</i>) and _{<i>O</i>4<i>'</i>}^1<i>'</i><i>T</i> (<i>C</i>1<i>'</i>- <i>endo</i>/<i>O</i>4<i>'</i>- <i>exo</i>) is found for the in silico model of dsTNA, while for the in silico model of dstPhoNA a B-type structure is found with a sugar puckering preference for _{<i>O</i>4<i>'</i>}^1<i>'</i><i>T</i> (<i>C</i>1<i>'</i>- <i>endo</i>/<i>O</i>4<i>'</i>- <i>exo</i>). Simulations with complementary DNA and RNA provided insight into the distinct pairing capabilities of TNA and tPhoNA.