On the Structure and Dynamics of Duplex GNA

Abstract

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.

Highly Stable Duplex Formation by Artificial Nucleic Acids Acyclic Threoninol Nucleic Acid (aTNA) and Serinol Nucleic Acid (SNA) with Acyclic Scaffolds

“…Especially for SNA, preorganization of the single strand is unlikely because both SNA/ a TNA and a TNA/ a TNA duplexes have almost the same CD spectra (Figure 5). Recently, Wiest and co‐workers suggested that the conformational flexibility inherent to a duplex of GNA also contributed to the decrease in entropy loss 26. However, because a TNA and SNA duplexes were not stabilized by the decrease in entropic loss like GNA but rather large enthalpic predilection, conformational flexibility is less important in these nucleic acids.…”

“…Recently, Wiest and co-workers suggested that the conformational flexibility inherent to a duplex of GNA also contributed to the decrease in entropy loss. [26] However, because aTNA and SNA duplexes were not stabilized by the decrease in entropic loss like GNA but rather large enthalpic predilection, conformational flexibility is less important in these nucleic acids. Flexibility of the scaffold should result in an entropic penalty relative to DNA and RNA duplexes.…”

The structural diversity of artificial genetic polymers

“…In the GNA family, the ( S )- and ( R )- enantiomers do not pair with each other and a structure for ( R )-GNA has not yet been reported. Nevertheless, the structure of ( S )-GNA provides a number of interesting observations that include cross-strand base stacking as opposed to the more common intrastrand base stacking and a strong hydrophobic effect from the 2′-methylene group ( 73 – 75 ). PNA is capable of forming a stable antiparallel duplex and can also cross-pair efficiently with DNA and RNA.…”

The Emergence of Life

“…More recently, the use of a simpler sugar, glycol, has been studied. It has been shown that the corresponding glycolic nucleic acid can form helical molecules, opening the possibility of a world of GNA (Chen et al 2009;Johnson et al 2011). Even a living world chemically closer to LUCA, but with the involvement of amyloid: an ANA world (amyloid nucleic acid) with nucleic acids bound to the amyloid protein has been considered .…”