While several unnatural base pair candidates have been identified, only few have been shown to be able to be efficient for central dogma process , among them, d5SICS (DS)-dNaM (DN) reported by Romesberg and coworkers, have been PCR amplified without sequence bias and efficiently transcribed in both directions. What makes the DS-DN UBP particularly interesting is that it forms an intercalated structure in duplex DNA and does not rely on complementary hydrogen bond formation for inter-strand pairing. The underlying cause of the unconventional orientations of DS-DN remains uncertain. It is yet to be verified whether the polymerase stabilizes the structure of the UBP-incorporated DNA, or if the UBP itself can be stabilized inside the DNA duplex.