A Simple γ-Backbone Modification Preorganizes Peptide Nucleic Acid into a Helical Structure
Abstract
Peptide nucleic acid (PNA) is a synthetic analogue of DNA and RNA, developed more than a decade ago in which the naturally occurring sugar phosphate backbone has been replaced by the N-(2-aminoethyl) glycine units. Unlike DNA or RNA in the unhybridized state (single strand) which can adopt a helical structure through base-stacking, although highly flexible, PNA does not have a well-defined conformational folding in solution. Herein, we show that a simple backbone modification at the gamma-position of the N-(2-aminoethyl) glycine unit can transform a randomly folded PNA into a helical structure. Spectroscopic studies showed that helical induction occurs in the C- to N-terminal direction and is sterically driven. This finding has important implication not only on the future design of nucleic acid mimics but also on the design of novel materials, where molecular organization and efficient electronic coupling are desired.
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The primer can be engineered to discriminate DNA's chirality using gamma-modified PNA.
“The achiral nature of PNA does not discriminate between d- or l-DNA; however, the primer can be engineered to discriminate DNA’s chirality using gamma-modified PNA42 which imparts chirality to the PNA primers.”
From Sequencing of <scp>d</scp>/<scp>l</scp>-DNA and XNA by Templated-Synthesis (2025) · cites this paper as [42]
The primers used contain chiral PNA residues that hybridize exclusively to d-DNA.
“However, the primers that were used contain chiral PNA residues22,41 that hybridize exclusively to d-DNA.42,43”
From Sequencing of <scp>d</scp>/<scp>l</scp>-DNA and XNA by Templated-Synthesis (2025) · cites this paper as [42]
Cites
Multicomponent Reactions with Isocyanides
Dömling, A. S. S., & Ugi, I. (2000) · Angewandte Chemie International Edition · doi:10.1002/1521-3773(20000915)39:18 · Cited by 4,079 · see citing works
Sequence-Selective Recognition of DNA by Strand Displacement with a Thymine-Substituted Polyamide
Nielsen, P. E., Egholm, M., Berg, R. H., & Buchardt, O. (1991) · Science · doi:10.1126/science.1962210 · Cited by 3,332 · see citing works
Gellman, S. H. (1998) · Accounts of Chemical Research · doi:10.1021/ar960298r · Cited by 2,507 · see citing works
Circular dichroism: Principles and applications
Jones, C. (1995) · FEBS Letters · doi:10.1016/0014-5793(95)90057-8 · Cited by 2,472 · see citing works
PNA hybridizes to complementary oligonucleotides obeying the Watson–Crick hydrogen-bonding rules
Egholm, M., Buchardt, O., Christensen, L., Behrens, C., Freier, S. M., Driver, D. A., Berg, R. H., Kim, S. K., Norden, B., & Nielsen, P. E. (1993) · Nature · doi:10.1038/365566a0 · Cited by 2,079 · see citing works
β-Peptides: From Structure to Function
Cheng, R. P., Gellman, S. H., & DeGrado, W. F. (2001) · Chemical Reviews · doi:10.1021/cr000045i · Cited by 1,866 · see citing works
Type-Specific Regulation of Adenylyl Cyclase by G Protein βγ Subunits
Tang, W.-J., & Gilman, A. G. (1991) · Science · doi:10.1126/science.1962211 · Cited by 1,091 · see citing works
Expression cloning of a mammalian proton-coupled oligopeptide transporter
Fei, Y.-J., Kanai, Y., Nußberger, S., Ganapathy, V., Leibach, F. H., Romero, M. F., Singh, S. K., Boron, W. F., & Hediger, M. A. (1994) · Nature · doi:10.1038/368563a0 · Cited by 890 · see citing works
Recognition of the DNA minor groove by pyrrole-imidazole polyamides
Dervan, P. B., & Edelson, B. S. (2003) · Current Opinion in Structural Biology · doi:10.1016/s0959-440x(03)00081-2 · Cited by 633 · see citing works
DNA-like double helix formed by peptide nucleic acid
Wittung-Stafshede, P. E., Nielsen, P. E., Buchardt, O., Egholm, M., & Nordén, B. (1994) · Nature · doi:10.1038/368561a0 · Cited by 504 · see citing works
van der Boom, T., Hayes, R. T., Zhao, Y., Bushard, P. J., Weiss, E. A., & Wasielewski, M. R. (2002) · Journal of the American Chemical Society · doi:10.1021/ja026286k · Cited by 390 · see citing works
Peptide Nucleic Acid. A Molecule with Two Identities
Nielsen, P. E. (1999) · Accounts of Chemical Research · doi:10.1021/ar980010t · Cited by 380 · see citing works
Wengel, J. (1998) · Accounts of Chemical Research · doi:10.1021/ar980051p · Cited by 335 · see citing works
Dueholm, K. L., Egholm, M., Behrens, C., et al. (1994) · The Journal of Organic Chemistry · doi:10.1021/jo00098a042 · Cited by 305 · see citing works
Hybridization of DNA and PNA Molecular Beacons to Single-Stranded and Double-Stranded DNA Targets
Kuhn, H., Demidov, V. V., Coull, J. M., et al. (2002) · Journal of the American Chemical Society · doi:10.1021/ja0041324 · Cited by 256 · see citing works
NMR Solution Structure of a Peptide Nucleic Acid Complexed with RNA
Brown, S. C., Thomson, S. A., Veal, J. M., & Davis, D. G. (1994) · Science · doi:10.1126/science.7519361 · Cited by 225 · see citing works
The absorption spectra of simple amides and peptides
Nielsen, E. B., & Schellman, J. A. (1967) · The Journal of Physical Chemistry · doi:10.1021/j100866a051 · Cited by 190 · see citing works
Bioinspired polymeric materials: in-between proteins and plastics
Barron, A. E., & Zuckerman, R. N. (1999) · Current Opinion in Chemical Biology · doi:10.1016/s1367-5931(99)00026-5 · Cited by 187 · see citing works
Chiral Studies across the Spectrum of Polymer Science
Green, M. M., Cheon, K., Yang, S., Park, J., Swansburg, S., & Liu, W. (2001) · Accounts of Chemical Research · doi:10.1021/ar010009l · Cited by 184 · see citing works
Conformationally Constrained PNA Analogues: Structural Evolution toward DNA/RNA Binding Selectivity
Kumar, V. A., & Ganesh, K. N. (2005) · Accounts of Chemical Research · doi:10.1021/ar030277e · Cited by 162 · see citing works
Menchise, V., Simone, G. D., Tedeschi, T., Corradini, R., Sforza, S., Marchelli, R., Capasso, D., Saviano, M., & Pedone, C. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2034746100 · Cited by 153 · see citing works
Beer, Niederalt, C., Grimme, S., et al. (2000) · PubMed · Cited by 133 · see citing works
Highly Specific DNA Recognition by a Designed Miniature Protein
Zondlo, N. J., & Schepartz, A. (1999) · Journal of the American Chemical Society · doi:10.1021/ja990968z · Cited by 129 · see citing works
Kinetics and mechanism of the DNA double helix invasion by pseudocomplementary peptide nucleic acids
Demidov, V. V., Protozanova, E., Izvolsky, K. I., et al. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.092127999 · Cited by 106 · see citing works
Energy Transfer in Calixarene-Based Cofacial-Positioned Perylene Bisimide Arrays
Hippius, C., Schlosser, F., Vysotsky, M. O., et al. (2006) · Journal of the American Chemical Society · doi:10.1021/ja058007+ · Cited by 106 · see citing works
A convenient synthesis of chiral peptide nucleic acid (PNA) monomers
Kosynkina, L. A., Wang, W., & Liang, T. C. (1994) · Tetrahedron Letters · doi:10.1016/s0040-4039(00)77056-0 · Cited by 100 · see citing works
Peptide Nucleic Acids with a Conformationally Constrained Chiral Cyclohexyl‐Derived Backbone
Lagriffoule, P., Eriksson, M., Jensen, K. K., et al. (1997) · Chemistry - A European Journal · doi:10.1002/chem.19970030613 · Cited by 92 · see citing works
Erratum: Lethal effect of the anti-Fas antibody in mice
Ogasawara, J., Watanabe‐Fukunaga, R., Adachi, M., et al. (1993) · Nature · doi:10.1038/365568a0 · Cited by 82 · see citing works
Englund, E. A., & Appella, D. H. (2005) · Organic Letters · doi:10.1021/ol051143z · Cited by 80 · see citing works
Pokorski, J. K., Witschi, M. A., Purnell, B. L., et al. (2004) · Journal of the American Chemical Society · doi:10.1021/ja046280q · Cited by 80 · see citing works
Peptide nucleic acid (PNA) with a chiral backbone based on alanine
Dueholm, K. L., Petersen, K. H., Jensen, D. K., et al. (1994) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/s0960-894x(01)80684-3 · Cited by 79 · see citing works
Convergent Synthesis of Peptide Nucleic Acids by Native Chemical Ligation
Dose, C., & Seitz, O. (2005) · Organic Letters · doi:10.1021/ol051489+ · Cited by 61 · see citing works
Tedeschi, T., Sforza, S., Corradini, R., et al. (2005) · Tetrahedron Letters · doi:10.1016/j.tetlet.2005.09.157 · Cited by 59 · see citing works
Govindaraju, T., Kumar, V. A., & Ganesh, K. N. (2005) · Journal of the American Chemical Society · doi:10.1021/ja044142v · Cited by 50 · see citing works
Tackett, A. J. (2002) · Nucleic Acids Research · doi:10.1093/nar/30.4.950 · Cited by 46 · see citing works
Self-Assembling Porphyrin-Modified Peptides
Dunetz, J. R., Sandstrom, C. K., Young, E. R., et al. (2005) · Organic Letters · doi:10.1021/ol050644h · Cited by 45 · see citing works
Davidson, M. G., Davies, R. P., Mitchell, H. J., et al. (1996) · Angewandte Chemie International Edition in English · doi:10.1002/anie.199619421 · Cited by 37 · see citing works
Self-Assembling of the Porphyrin-Linked Acyclic Penta- and Heptapeptides in Aqueous Trifluoroethanol
Arai, T., Inudo, M., Ishimatsu, T., et al. (2003) · The Journal of Organic Chemistry · doi:10.1021/jo030001k · Cited by 26 · see citing works
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Momin, M. Y., Gaddam, R. R., Kravitz, M., Gupta, A., & Vikram, A. (2021) · Cells · doi:10.3390/cells10113097 · Cited by 107 · see citing works
PNA as a Biosupramolecular Tag for Programmable Assemblies and Reactions
Barluenga, S., & Winssinger, N. (2015) · Accounts of Chemical Research · doi:10.1021/acs.accounts.5b00109 · Cited by 77 · see citing works
Chang, D., Lindberg, E., & Winssinger, N. (2017) · Journal of the American Chemical Society · doi:10.1021/jacs.6b12764 · Cited by 72 · see citing works
Kim, K. T., Angerani, S., Chang, D., & Winssinger, N. (2019) · Journal of the American Chemical Society · doi:10.1021/jacs.9b05688 · Cited by 52 · see citing works
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Nimmagadda, A., Shi, Y., & Cai, J. (2019) · Current Medicinal Chemistry · doi:10.2174/0929867324666171107095913 · Cited by 21 · see citing works
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Sequencing of <scp>d</scp>/<scp>l</scp>-DNA and XNA by Templated-Synthesis
Joshi, S., Romanens, P., & Winssinger, N. (2025) · Journal of the American Chemical Society · doi:10.1021/jacs.5c00708 · Cited by 4 · see citing works
- Authors
- Dragulescu-Andrasi, A., Rapireddy, S., Frezza, B. M., Gayathri, C., Gil, R. R., & Ly, D. H.
- Affiliations
- Contribution from the Department of Chemistry, Carnegie Mellon University, 4400 Fifth Avenue, Pittsburgh, Pennsylvania 15213
- Carnegie Mellon University (US)
- Venue
- Journal of the American Chemical Society
- Publisher
- American Chemical Society (ACS)
- Published
- 2006-07-19
- Volume
- 128
- Issue
- 31
- Pages
- 10258-10267
- ISSN
- 0002-7863 (ISSN-L)
- 1520-5126
- OpenAlex
- W2040054282
- Cited by
- 286
- References
- 38
- Citations by year
- 2026: 17 · 2025: 12 · 2024: 16 · 2023: 15 · 2022: 18 · 2021: 18 · 2020: 23 · 2019: 16 · 2018: 18 · 2017: 18 · 2016: 16 · 2015: 15 · 2014: 11 · 2013: 12 · 2012: 18
- FWCI
- 2.84
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of the American Chemical Society (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Division of Chemistry
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA and Nucleic Acid Chemistry
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Advanced biosensing and bioanalysis techniques
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Keywords
- peptide nucleic acid, helical conformation, backbone modification, steric effects, nucleic acid mimics, electronic coupling
- MeSH terms
- Circular Dichroism, Models, Molecular, Nucleic Acid Conformation, Temperature, Dimerization, Nuclear Magnetic Resonance, Biomolecular, Peptide Nucleic Acids
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