The structural diversity of artificial genetic polymers

Synthetic genetics is a subdiscipline of synthetic biology that aims to develop artificial genetic polymers (also referred to as xeno-nucleic acids or XNAs) that can replicate in vitro and eventually in model cellular organisms. This field of science combines organic chemistry with polymerase engineering to create alternative forms of DNA that can store genetic information and evolve in response to external stimuli. Practitioners of synthetic genetics postulate that XNA could be used to safeguard synthetic biology organisms by storing genetic information in orthogonal chromosomes. XNA polymers are also under active investigation as a source of nuclease resistant affinity reagents (aptamers) and catalysts (xenozymes) with practical applications in disease diagnosis and treatment. In this review, we provide a structural perspective on known antiparallel duplex structures in which at least one strand of the Watson–Crick duplex is composed entirely of XNA. Currently, only a handful of XNA structures have been archived in the Protein Data Bank as compared to the more than 100 000 structures that are now available. Given the growing interest in xenobiology projects, we chose to compare the structural features of XNA polymers and discuss their potential to access new regions of nucleic acid fold space.

[1]  Z. Wawrzak,et al.  Why does TNA cross-pair more strongly with RNA than with DNA? an answer from X-ray analysis. , 2003, Angewandte Chemie.

[2]  D. G. Davis,et al.  NMR solution structure of a peptide nucleic acid complexed with RNA. , 1994, Science.

[3]  R. Esnouf,et al.  Solution structure of a HNA-RNA hybrid. , 2000, Chemistry & biology.

[4]  M. Frank-Kamenetskii,et al.  Base-stacking and base-pairing contributions into thermal stability of the DNA double helix , 2006, Nucleic acids research.

[5]  M. Yusupov,et al.  High-resolution structure of the eukaryotic 80S ribosome. , 2014, Annual review of biochemistry.

[6]  S. Yokoyama,et al.  Generation of high-affinity DNA aptamers using an expanded genetic alphabet , 2013, Nature Biotechnology.

[7]  R. Mann,et al.  Origins of specificity in protein-DNA recognition. , 2010, Annual review of biochemistry.

[8]  H M Berman,et al.  Conformations of the sugar-phosphate backbone in helical DNA crystal structures. , 1997, Biopolymers.

[9]  David R. Liu,et al.  Recent progress toward the templated synthesis and directed evolution of sequence-defined synthetic polymers. , 2009, Chemistry & biology.

[10]  Peter Scholz,et al.  Chemical Etiology of Nucleic Acid Structure: The α-Threofuranosyl-(3'→2') Oligonucleotide System , 2000 .

[11]  A. Noronha,et al.  Synthesis and biophysical properties of arabinonucleic acids (ANA): circular dichroic spectra, melting temperatures, and ribonuclease H susceptibility of ANA.RNA hybrid duplexes. , 2000, Biochemistry.

[12]  Jianmin Gao,et al.  A Four-Base Paired Genetic Helix with Expanded Size , 2003, Science.

[13]  Joanne I. Yeh,et al.  The crystal structure of non-modified and bipyridine-modified PNA duplexes. , 2010, Chemistry.

[14]  P. Nielsen,et al.  Solution structure of a peptide nucleic acid–DNA duplex , 1996, Nature Structural Biology.

[15]  John C. Chaput,et al.  Synthetic Genetic Polymers Capable of Heredity and Evolution , 2012, Science.

[16]  P. Auffinger,et al.  Nucleic acid solvation: from outside to insight. , 2007, Current opinion in structural biology.

[17]  H. Schwalbe,et al.  NMR Spectroscopy of RNA , 2003, Chembiochem : a European journal of chemical biology.

[18]  H. Schwalbe,et al.  NMR Spectroscopy of RNA , 2003, Chembiochem : a European journal of chemical biology.

[19]  M. Damha,et al.  Polymerase-Directed Synthesis of 2‘-Deoxy-2‘-fluoro-β-D-arabinonucleic Acids , 2007 .

[20]  L. James Maher,et al.  Mechanical properties of DNA-like polymers , 2013, Nucleic acids research.

[21]  E. Meggers,et al.  Duplex Structure of a Minimal Nucleic Acid , 2008, Journal of the American Chemical Society.

[22]  J. Chaput,et al.  A DNA pentaplex incorporating nucleobase quintets. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[23]  Struther Arnott,et al.  The structure of B-DNA in oriented fibers. , 1996, Journal of biomolecular structure & dynamics.

[24]  T. N. Bhat,et al.  The Protein Data Bank , 2000, Nucleic Acids Res..

[25]  J. Wengel,et al.  Xylo-Configured oligonucleotides (XNA, xylo nucleic acid): synthesis of conformationally restricted derivatives and hybridization towards DNA and RNA complements. , 2003, Bioorganic & medicinal chemistry letters.

[26]  R. Gil,et al.  Solution structure of a peptide nucleic acid duplex from NMR data: features and limitations. , 2008, Journal of the American Chemical Society.

[27]  G. Portella,et al.  Backbone FC-H···O hydrogen bonds in 2'F-substituted nucleic acids. , 2013, Angewandte Chemie.

[28]  Thomas Lavergne,et al.  A Semi-Synthetic Organism with an Expanded Genetic Alphabet , 2014, Nature.

[29]  P. Nielsen,et al.  PNA-nucleic acid complexes. Structure, stability and dynamics , 1996, Quarterly Reviews of Biophysics (print).

[30]  Enzymatic Recognition of 2′‐Modified Ribonucleoside 5′‐Triphosphates: Towards the Evolution of Versatile Aptamers , 2012, Chembiochem : a European journal of chemical biology.

[31]  J. Wengel,et al.  NMR studies of fully modified locked nucleic acid (LNA) hybrids: solution structure of an LNA:RNA hybrid and characterization of an LNA:DNA hybrid. , 2004, Bioconjugate chemistry.

[32]  S. Balasubramanian,et al.  5-Formylcytosine alters the structure of the DNA double helix , 2014, Nature Structural &Molecular Biology.

[33]  G. Michael Blackburn,et al.  Nucleic acids in chemistry and biology , 2007 .

[34]  A. Eschenmoser,et al.  Warum pentose-und nicht hexose-nucleinsäuren? Teil III. Oligo(2′,3′-dideoxy-β-D-glucopyranosyl) nucleotide (‘homo-DNS’): Paarungesigenschaften†‡ , 1993 .

[35]  O. Wiest,et al.  On the structure and dynamics of duplex GNA. , 2011, The Journal of organic chemistry.

[36]  Randy J Read,et al.  Crystal structure of double helical hexitol nucleic acids. , 2002, Journal of the American Chemical Society.

[37]  J. Doudna,et al.  Insights into RNA structure and function from genome-wide studies , 2014, Nature Reviews Genetics.

[38]  Philippe Marlière,et al.  Chemical evolution of a bacterium's genome. , 2011, Angewandte Chemie.

[39]  Poul Nielsen,et al.  LNA (Locked Nucleic Acids): Synthesis of the adenine, cytosine, guanine, 5-methylcytosine, thymine and uracil bicyclonucleoside monomers, oligomerisation, and unprecedented nucleic acid recognition , 1998 .

[40]  Jeremy N. S. Evans.  Biomolecular NMR Spectroscopy , 1995 .

[41]  M. Manoharan,et al.  X-ray crystallographic analysis of the hydration of A- and B-form DNA at atomic resolution. , 1998, Biopolymers.

[42]  V. Larue,et al.  Solution conformation of an RNA--DNA hybrid duplex containing a pyrimidine RNA strand and a purine DNA strand. , 2001, International journal of biological macromolecules.

[43]  C. Ban,et al.  A single 2'-hydroxyl group converts B-DNA to A-DNA. Crystal structure of the DNA-RNA chimeric decamer duplex d(CCGGC)r(G)d(CCGG) with a novel intermolecular G-C base-paired quadruplet. , 1994, Journal of molecular biology.

[44]  Wei Yang,et al.  Crystal Structures of RNase H Bound to an RNA/DNA Hybrid: Substrate Specificity and Metal-Dependent Catalysis , 2005, Cell.

[45]  J. Chaput,et al.  Synthesis of two mirror image 4-helix junctions derived from glycerol nucleic acid. , 2008, Journal of the American Chemical Society.

[46]  M. Egli,et al.  Insights from crystallographic studies into the structural and pairing properties of nucleic acid analogs and chemically modified DNA and RNA oligonucleotides. , 2007, Annual review of biophysics and biomolecular structure.

[47]  M. Manoharan,et al.  2'-Fluoroarabino- and arabinonucleic acid show different conformations, resulting in deviating RNA affinities and processing of their heteroduplexes with RNA by RNase H. , 2006, Biochemistry.

[48]  E. Meggers,et al.  Atomic resolution duplex structure of the simplified nucleic acid GNA. , 2010, Chemical communications.

[49]  J. Chaput.  Replicating an Expanded Genetic Alphabet in Cells , 2014, Chembiochem : a European journal of chemical biology.

[50]  M. Egli,et al.  The long and winding road to the structure of homo-DNA. , 2007, Chemical Society reviews.

[51]  M. Manoharan,et al.  Unexpected origins of the enhanced pairing affinity of 2′-fluoro-modified RNA , 2010, Nucleic acids research.

[52]  P. Herdewijn,et al.  Solution structure and conformational dynamics of deoxyxylonucleic acids (dXNA): an orthogonal nucleic acid candidate. , 2012, Chemistry.

[53]  S E Ealick,et al.  Advances in multiple wavelength anomalous diffraction crystallography. , 2000, Current opinion in chemical biology.

[54]  C. Betzel,et al.  The crystal structure of an ‘All Locked’ nucleic acid duplex , 2010, Nucleic acids research.

[55]  A. Eschenmoser.  Etiology of potentially primordial biomolecular structures: from vitamin B12 to the nucleic acids and an inquiry into the chemistry of life's origin: a retrospective. , 2011, Angewandte Chemie.

[56]  G. Portella,et al.  Differential stability of 2′F-ANA•RNA and ANA•RNA hybrid duplexes: roles of structure, pseudohydrogen bonding, hydration, ion uptake and flexibility , 2010, Nucleic acids research.

[57]  Andrea Schmidt,et al.  On the routine use of soft X-rays in macromolecular crystallography. Part IV. Efficient determination of anomalous substructures in biomacromolecules using longer X-ray wavelengths. , 2007, Acta crystallographica. Section D, Biological crystallography.

[58]  K. Breslauer,et al.  The contribution of DNA single-stranded order to the thermodynamics of duplex formation. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[59]  P. Herdewijn,et al.  Xylonucleic acid: synthesis, structure, and orthogonal pairing properties , 2015, Nucleic acids research.

[60]  Vitor B. Pinheiro,et al.  Towards XNA nanotechnology: new materials from synthetic genetic polymers , 2014, Trends in biotechnology.

[61]  J. Watts,et al.  Energetically important C-H···F-C pseudohydrogen bonding in water: evidence and application to rational design of oligonucleotides with high binding affinity. , 2011, Journal of the American Chemical Society.

[62]  Jacques H. van Boom,et al.  Molecular structure of a left-handed double helical DNA fragment at atomic resolution , 1979, Nature.

[63]  John C Chaput,et al.  The emerging world of synthetic genetics. , 2012, Chemistry & biology.

[64]  D. Klostermeier,et al.  RNA Structure and Folding: Biophysical Techniques and Prediction Methods , 2013 .

[65]  J. Szostak,et al.  Kinetic Analysis of an Efficient DNA-Dependent TNA Polymerase , 2005, Journal of the American Chemical Society.

[66]  C. Wilds,et al.  2'-Deoxy-2'-fluoro-beta-D-arabinonucleosides and oligonucleotides (2'F-ANA): synthesis and physicochemical studies. , 2000, Nucleic acids research.

[67]  Martin Egli,et al.  Crystallographic Studies of Chemically Modified Nucleic Acids: A Backward Glance , 2010, Chemistry & biodiversity.

[68]  Julia Brasch,et al.  Structures from Anomalous Diffraction of Native Biological Macromolecules , 2012, Science.

[69]  John C Chaput,et al.  DNA polymerase-mediated DNA synthesis on a TNA template. , 2003, Journal of the American Chemical Society.

[70]  M. Egli,et al.  Consequences of Replacing the DNA 3‘-Oxygen by an Amino Group: High-Resolution Crystal Structure of a Fully Modified N3‘ → P5‘ Phosphoramidate DNA Dodecamer Duplex† , 1998 .

[71]  P. Herdewijn,et al.  Enantiomeric selection properties of β-homoDNA: enhanced pairing for heterochiral complexes. , 2013, Angewandte Chemie.

[72]  J. Feigon,et al.  Solution structure of a parallel-stranded oligoisoguanine DNA pentaplex formed by d(T(iG)4 T) in the presence of Cs+ ions. , 2012, Angewandte Chemie.

[73]  T. Hökfelt,et al.  Potent and nontoxic antisense oligonucleotides containing locked nucleic acids. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[74]  P. Scholz,et al.  Chemical etiology of nucleic acid structure: the alpha-threofuranosyl-(3'-->2') oligonucleotide system. , 2000, Science.

[75]  D. Appella.  Non-natural nucleic acids for synthetic biology. , 2009, Current opinion in chemical biology.

[76]  John C Chaput,et al.  Darwinian evolution of an alternative genetic system provides support for TNA as an RNA progenitor. , 2012, Nature chemistry.

[77]  M. Weiss,et al.  Crystallographic analysis of a sex-specific enhancer element: sequence-dependent DNA structure, hydration, and dynamics. , 2009, Journal of molecular biology.

[78]  A. Rich,et al.  Crystal structure of an Okazaki fragment at 2-A resolution. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[79]  P. Herdewijn,et al.  Chemistry and biology of artificial nucleic acids , 2012 .

[80]  P. Herdewijn,et al.  The crystal structure of the CeNA:RNA hybrid ce(GCGTAGCG):r(CGCUACGC). , 2011, Chemistry.

[81]  R. Pattanayek,et al.  Crystal structure of homo-DNA and nature's choice of pentose over hexose in the genetic system. , 2006, Journal of the American Chemical Society.

[82]  Weihong Tan,et al.  In vitro selection with artificial expanded genetic information systems , 2013, Proceedings of the National Academy of Sciences.

[83]  A. Eschenmoser,et al.  Warum Pentose- und nicht Hexose-Nucleinsäuren??. Teil II. Oligonucleotide aus 2′,3′-Dideoxy-β-D-glucopyranosyl-Bausteinen (‘Homo-DNS’): Herstellung.† , 1992 .

[84]  M. Egli,et al.  The many twists and turns of DNA: template, telomere, tool, and target. , 2010, Current opinion in structural biology.

[85]  B. Rupp.  Biomolecular Crystallography: Principles, Practice, and Application to Structural Biology , 2009 .

[86]  Z. Dauter,et al.  Phosphates in the Z-DNA dodecamer are flexible, but their P-SAD signal is sufficient for structure solution. , 2014, Acta crystallographica. Section D, Biological crystallography.

[87]  Eric Meggers,et al.  A simple glycol nucleic acid. , 2005, Journal of the American Chemical Society.

[88]  M. Egholm,et al.  Sequence-selective recognition of DNA by strand displacement with a thymine-substituted polyamide. , 1991, Science.

[89]  E. Ennifar.  Nucleic Acid Crystallography , 2016, Methods in Molecular Biology.

[90]  P. Champ,et al.  Distributions of Z-DNA and nuclear factor I in human chromosome 22: a model for coupled transcriptional regulation. , 2004, Nucleic acids research.

[91]  J. Chaput,et al.  An efficient and faithful in vitro replication system for threose nucleic acid. , 2013, Journal of the American Chemical Society.

[92]  B. Mooers,et al.  The crystal structure of an oligo(U):pre-mRNA duplex from a trypanosome RNA editing substrate. , 2011, RNA.

[93]  W. Olson,et al.  A-form conformational motifs in ligand-bound DNA structures. , 2000, Journal of molecular biology.

[94]  J. DeStefano,et al.  Selection of 2′-deoxy-2′-fluoroarabinonucleotide (FANA) aptamers that bind HIV-1 reverse transcriptase with picomolar affinity , 2015, Nucleic acids research.

[95]  K. G. Rajeev,et al.  Unique gene-silencing and structural properties of 2'-fluoro-modified siRNAs. , 2011, Angewandte Chemie.

[96]  M. Ebert,et al.  Oligonucleotides with Sugars Other Than Ribo‐ and 2′‐Deoxyribofuranose in the Backbone: the Solution Structures Determined by NMR in the Context of the ‘Etiology of Nucleic Acids’ Project of Albert Eschenmoser , 2010, Chemistry & biodiversity.

[97]  J. Wengel,et al.  Enzymatic Incorporation of LNA Nucleotides into DNA Strands , 2007, Chembiochem : a European journal of chemical biology.

[98]  Wolfram Saenger,et al.  Principles of Nucleic Acid Structure , 1983 .

[99]  M. Ebert,et al.  The structure of a TNA-TNA complex in solution: NMR study of the octamer duplex derived from alpha-(L)-threofuranosyl-(3'-2')-CGAATTCG. , 2008, Journal of the American Chemical Society.

[100]  P. Nielsen,et al.  Crystal structure of a peptide nucleic acid (PNA) duplex at 1.7 Å resolution , 1997, Nature Structural Biology.

[101]  Carlos González,et al.  The solution structure of double helical arabino nucleic acids (ANA and 2′F-ANA): effect of arabinoses in duplex-hairpin interconversion , 2012, Nucleic acids research.

[102]  P. Herdewijn,et al.  Difference in conformational diversity between nucleic acids with a six-membered 'sugar' unit and natural 'furanose' nucleic acids. , 2003, Nucleic acids research.

[103]  Vitor B. Pinheiro,et al.  Catalysts from synthetic genetic polymers , 2014, Nature.

[104]  D. F. Koenig,et al.  Structure of hen egg-white lysozyme. A three-dimensional Fourier synthesis at 2 Angstrom resolution. , 1965, Nature.

[105]  Stephen Neidle,et al.  Principles of nucleic acid structure , 2007 .

[106]  Jens Kurreck,et al.  Nucleic acids chemistry and biology. , 2003, Angewandte Chemie.

[107]  Marc C Nicklaus,et al.  PROSIT, AN ONLINE SERVICE TO CALCULATE PSEUDOROTATIONAL PARAMETERS OF NUCLEOSIDES AND NUCLEOTIDES , 2005, Nucleosides, nucleotides & nucleic acids.

[108]  J. Szostak,et al.  TNA synthesis by DNA polymerases. , 2003, Journal of the American Chemical Society.

[109]  M. Manoharan,et al.  2'-Fluoro RNA shows increased Watson-Crick H-bonding strength and stacking relative to RNA: evidence from NMR and thermodynamic data. , 2012, Angewandte Chemie.

[110]  P. Herdewijn,et al.  Recognition of threosyl nucleotides by DNA and RNA polymerases. , 2003, Nucleic acids research.

[111]  G. Taylor.  The phase problem. , 2003, Acta crystallographica. Section D, Biological crystallography.

[112]  F. Romesberg,et al.  The expanded genetic alphabet. , 2015, Angewandte Chemie.

[113]  Peter E. Nielsen,et al.  PNA hybridizes to complementary oligonucleotides obeying the Watson–Crick hydrogen-bonding rules , 1993, Nature.

[114]  P. D. Cook,et al.  Crystal structure and improved antisense properties of 2'-O-(2-methoxyethyl)-RNA , 1999, Nature Structural Biology.