Isotactic Glycero Oligothymidylate. a Convenient Preparation of (R) and (S) 1′, 2′-Seco 2′-Nor Thymidine

Azymah, Muhammad; Chavis, C.; Lucas, Marc; Morvan, François; Imbach, Jean‐Louis

doi:10.1080/07328319208018339

“…Previous experiments with acyclic nucleotides in DNA revealed that adding one or more acyclic nucleotides to oligodeoxynucleotides resulted in strong thermal duplex destabilizations. This was attributed to lacking conformational preorganization of the more flexible acyclic nucleotides in single strands resulting in a significant entropic penalty upon duplex formation. − …”

Section: Introductionmentioning

confidence: 99%

On the Structure and Dynamics of Duplex GNA

Johnson

¹

,

Schlegel

²

,

Meggers

³

et al. 2011

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Glycol nucleic acid (GNA), with a nucleotide backbone comprising of just three carbons and the stereocenter derived from propylene glycol (1,2-propanediol), is a structural analog of nucleic acids with intriguing biophysical properties, such as formation of highly stable antiparallel duplexes with high Watson-Crick base pairing fidelity. Previous crystallographic studies of double stranded GNA (dsGNA) indicated two forms of backbone conformations, an elongated M-type (containing metallo-base pairs) and the condensed N-type (containing brominated base pairs). A herein presented new crystal structure of a GNA duplex at 1.8 Å resolution from self-complementary 3'-CTC(Br)UAGAG-2' GNA oligonucleotides reveals an N-type conformation with alternating gauche-anti torsions along its (O3'-C3'-C2'-O2') backbone. To elucidate the conformational state of dsGNA in solution, molecular dynamic simulations over a period of 20 ns were performed with the now available repertoire of structural information. Interestingly, dsGNA adopts conformational states in solution intermediate between experimentally observed backbone conformations: simulated dsGNA shows the all-gauche conformation characteristic of M-type GNA with the higher helical twist common to N-type GNA structures. The so far counterintuitive, smaller loss of entropy upon duplex formation as compared to DNA can be traced back to the conformational flexibility inherent to dsGNA but missing in dsDNA. Besides extensive interstrand base stacking and conformational preorganization of single strands, this flexibility contributes to the extraordinary thermal stability of GNA.

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“…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.…”

mentioning

confidence: 99%

Insight into the High Duplex Stability of the Simplified Nucleic Acid GNA

Schlegel

¹

,

Xie

²

,

Zhang

³

et al. 2009

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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

show abstract

Insight into the High Duplex Stability of the Simplified Nucleic Acid GNA

Schlegel

¹

,

Xie

²

,

Zhang

³

et al. 2009

View full text Add to dashboard Cite

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

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Isotactic Glycero Oligothymidylate. a Convenient Preparation of (R) and (S) 1′, 2′-Seco 2′-Nor Thymidine

Cited by 19 publications

References 16 publications

On the Structure and Dynamics of Duplex GNA

On the Structure and Dynamics of Duplex GNA

Insight into the High Duplex Stability of the Simplified Nucleic Acid GNA

Insight into the High Duplex Stability of the Simplified Nucleic Acid GNA

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