More than 50 years after Watson and Crick unraveled the secondary structure of the canonical B-form DNA duplex, the function of the pyrimidine-purine nucleobase pairing and the importance of the charged phosphodiester backbone are well established.[1] However, the chemical and evolutionary necessity for the rather complicated deoxyribose and ribose moiety in the backbone of DNA and RNA, respectively, is still uncertain.[2] To address this question, researchers have investigated nucleic acids with alternative sugar residues. [3][4][5] In the course of searching for structurally simplified nucleic acid backbones, we discovered recently that a glycol nucleic acid (GNA) with an acyclic propylene glycol phosphodiester backbone can form stable antiparallel duplexes in a Watson-Crick fashion. [6][7][8][9] The constitution of the GNA backbone as well as a newly published GNA-duplex structure are shown in Figure 1.[9] The glycol nucleotide building blocks contain just three carbon atoms and one stereocenter, and are connected by phosphodiester bonds. GNA combines structural simplicity and atom economy with a high duplex stability that significantly exceeds the stabilities of analogous duplexes of DNA and RNA. These features not only make GNA a possible genetic molecule for initial life on Earth but also an interesting scaffold for nucleic acid derived nanotechnology.For almost the last two decades, it had been widely assumed that nucleic acid analogues containing a phosphodiester backbone need to be cyclic to produce the required conformational preorganization of the individual strands for the formation of a stable duplex. [10,11] The high duplex stability of GNA therefore appears very surprising. In fact, GNA is to date the only known phosphodiester-based nucleic acid with an acyclic backbone that is capable of forming stable duplexes. Herein we present data that resolve this apparent discrepancy between the acyclic nature of the GNA backbone and the high stability of GNA duplexes.To gain insight into the reason for the high duplex stability of GNA, we began by determining the thermodynamic parameters of duplex formation. Accordingly, the values of DG (Gibbs free energy), DH (change in enthalpy), and DS (change in entropy)were obtained from vant Hoff plots by charting the reciprocal of the melting temperature, T m , against the natural logarithm of varying duplex concentrations for three GNA duplexes and comparison with DNA duplexes with the same sequences ( Table 1). As expected, the higher thermal stabilities of GNA duplexes correlate with higher thermodynamic stabilities (298 K).[8] However, surprisingly, for all three duplexes we found that GNA-duplex formation is less exothermic than DNA-duplex formation, but at the same time entropically significantly less unfavorable. This entropic advantage is counterintuitive, since one would expect that an acyclic backbone is more flexible and thus entropically unfavorable for duplex formation. ÀT DS (298 K) [b] [kcal mol À1