Enhanced functional potential of nucleic acid aptamer libraries patterned to increase secondary structure
Open accessAbstract
The in vitro selection of nucleic acid libraries has driven the discovery of RNA and DNA receptors (aptamers) and catalysts with tailor-made functional properties. Functional nucleic acids emerging from selections have been observed to possess an unusually high degree of secondary structure. In this study, we experimentally examined the relationship between the degree of secondary structure in a nucleic acid library and its ability to yield aptamers that bind protein targets. We designed a patterned nucleic acid library (denoted R*Y*) to enhance the formation of stem-loop structures without imposing any specific sequence or secondary structural requirement. This patterned library was predicted computationally to contain a significantly higher average folding energy compared to a standard, unpatterned N(60) library of the same length. We performed three different iterated selections for protein binding using patterned and unpatterned libraries competing in the same solution. In all three cases, the patterned R*Y* library was enriched relative to the unpatterned library over the course of the 9- to 10-round selection. Characterization of individual aptamer clones emerging from the three selections revealed that the highest affinity aptamer assayed arose from the patterned library for two protein targets, while in the third case, the highest affinity aptamers from the patterned and random libraries exhibited comparable affinity. We identified the binding motif requirements for the most active aptamers generated against two of the targets. The two binding motifs are 3.4- and 27-fold more likely to occur in the R*Y* library than in the N(60) library. Collectively, our findings suggest that researchers performing selections for nucleic acid aptamers and catalysts should consider patterned libraries rather than commonly used N(m) libraries to increase both the likelihood of isolating functional molecules and the potential activities of the resulting molecules.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Stable folding is believed to be a prerequisite for function.
“While stable folding is believed to be a prerequisite for function (46), Ck is not a perfect predictor of function.”
From Prebiotically plausible mechanisms increase compositional diversity of nucleic acid sequences (2012) · cites this paper as [46]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Selection of single-stranded DNA molecules that bind and inhibit human thrombin
Bock, L. C., Griffin, L. C., Latham, J. A., Vermaas, E. H., & Toole, J. J. (1992) · Nature · doi:10.1038/355564a0 · Cited by 2,460 · see citing works
Twenty-Five Years of Quantitative PCR for Gene Expression Analysis
VanGuilder, H. D., Vrana, K. E., & Freeman, W. M. (2008) · BioTechniques · doi:10.2144/000112776 · Cited by 1,246 · see citing works
Ellington, A. D., & Szostak, J. W. (1992) · Nature · doi:10.1038/355850a0 · Cited by 858 · see citing works
The Chemical Biology of Aptamers
Mayer, G. (2009) · Angewandte Chemie International Edition · doi:10.1002/anie.200804643 · Cited by 591 · see citing works
Riboswitches as versatile gene control elements
Tucker, B. J., & Breaker, R. R. (2005) · Current Opinion in Structural Biology · doi:10.1016/j.sbi.2005.05.003 · Cited by 546 · see citing works
Directed Evolution of Nucleic Acid Enzymes
Joyce, G. F. (2004) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.73.011303.073717 · Cited by 515 · see citing works
Wong, I., & Lohman, T. M. (1993) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.90.12.5428 · Cited by 390 · see citing works
High-affinity oligonucleotide ligands to human IgE inhibit binding to Fc ε receptor I
Wiegand, T. W., Williams, P. B., Dreskin, S. C., Jouvin, M., Kinet, J., & Tasset, D. M. (1996) · The Journal of Immunology · doi:10.4049/jimmunol.157.1.221 · Cited by 348 · see citing works
RNA Structure: Reading the Ribosome
Noller, H. F. (2005) · Science · doi:10.1126/science.1111771 · Cited by 345 · see citing works
Xiong, H., Buckwalter, B. L., Shieh, H., & Hecht, M. H. (1995) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.92.14.6349 · Cited by 269 · see citing works
Informational Complexity and Functional Activity of RNA Structures
Carothers, J. M., Oestreich, S. C., Davis, J. H., & Szostak, J. W. (2004) · Journal of the American Chemical Society · doi:10.1021/ja031504a · Cited by 237 · see citing works
Let's get specific: the relationship between specificity and affinity
Eaton, B. E., Gold, L., & Zichi, D. A. (1995) · Chemistry & Biology · doi:10.1016/1074-5521(95)90023-3 · Cited by 218 · see citing works
A deoxyribozyme that harnesses light to repair thymine dimers in DNA
Chinnapen, D. J. ‐., & Sen, D. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0305943101 · Cited by 190 · see citing works
Inhibition of receptor binding by high-affinity RNA ligands to vascular endothelial growth factor
Jellinek, D., Green, L. S., Bell, C., & Janjić, N. (1994) · Biochemistry · doi:10.1021/bi00200a028 · Cited by 184 · see citing works
Wlotzka, B., Leva, S., Eschgfäller, B., Burmeister, J., Kleinjung, F., Kaduk, C., Muhn, P., Hess‐Stumpp, H., & Klußmann, S. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.132067399 · Cited by 183 · see citing works
Isolation of high-affinity GTP aptamers from partially structured RNA libraries
Davis, J. H., & Szostak, J. W. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.182095699 · Cited by 179 · see citing works
Deoxyribozymes: useful DNA catalysts in vitro and in vivo
Baum, D. A., & Silverman, S. K. (2008) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-008-8029-y · Cited by 174 · see citing works
In silico selection of RNA aptamers
Chushak, Y. G., & Stone, M. O. (2009) · Nucleic Acids Research · doi:10.1093/nar/gkp408 · Cited by 156 · see citing works
A Ribozyme for the Aldol Reaction
Fusz, S., Eisenführ, A., Srivatsan, S. G., Heckel, A., & Famulok, M. (2005) · Chemistry & Biology · doi:10.1016/j.chembiol.2005.06.008 · Cited by 143 · see citing works
Aptamers selected for higher-affinity binding are not more specific for the target ligand
Carothers, J. M., Oestreich, S. C., & Szostak, J. W. (2006) · Journal of the American Chemical Society · doi:10.1021/ja060952q · Cited by 132 · see citing works
Hicke, B. J., Watson, S. R., Koenig, A. L., Lynott, C. K., Bargatze, R. F., Chang, Y.-F., Ringquist, S., Moon-McDermott, L., Jennings, S. D., Fitzwater, T., et al. (1996) · Journal of Clinical Investigation · doi:10.1172/jci119092 · Cited by 132 · see citing works
The secondary structure and sequence optimization of an RNA ligase ribozyme
Ekland, E. H., & Bartel, D. P. (1995) · Nucleic Acids Research · doi:10.1093/nar/23.16.3231 · Cited by 127 · see citing works
Exploring the sequence space of a DNA aptamer using microarrays
Katilius, E., Flores, C. L., & Woodbury, N. W. (2007) · Nucleic Acids Research · doi:10.1093/nar/gkm922 · Cited by 119 · see citing works
RNA catalysis: ribozymes, ribosomes, and riboswitches
Strobel, S. A., & Cochrane, J. C. (2007) · Current Opinion in Chemical Biology · doi:10.1016/j.cbpa.2007.09.010 · Cited by 118 · see citing works
DNA and RNA Can Be Equally Efficient Catalysts for Carbon−Carbon Bond Formation
Chandra, M., & Silverman, S. K. (2008) · Journal of the American Chemical Society · doi:10.1021/ja7111965 · Cited by 115 · see citing works
Calcium-dependent oligonucleotide antagonists specific for L-selectin.
O'Connell, D., Koenig, A. L., Jennings, S. D., Hicke, B. J., Han, H., Fitzwater, T., Chang, Y.-F., Varki, N. M., Parma, D. H., & Varki, A. P. (1996) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.93.12.5883 · Cited by 113 · see citing works
Bing, T., Yang, X., Mei, H., et al. (2010) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2010.01.054 · Cited by 109 · see citing works
Isolation of a fluorophore-specific DNA aptamer with weak redox activity
Wilson, C., & Szostak, J. W. (1998) · Chemistry & Biology · doi:10.1016/s1074-5521(98)90289-7 · Cited by 107 · see citing works
Sen, D., & Geyer, C. R. (1998) · Current Opinion in Chemical Biology · doi:10.1016/s1367-5931(98)80103-8 · Cited by 104 · see citing works
Nucleic acid evolution and minimization by nonhomologous random recombination
Bittker, J. A., Le, B. V., & Liu, D. R. (2002) · Nature Biotechnology · doi:10.1038/nbt736 · Cited by 89 · see citing works
Self-citationReduction of an Aldehyde by a NADH/Zn 2+ -Dependent Redox Active Ribozyme
Tsukiji, S., Pattnaik, S., & Suga, H. (2004) · Journal of the American Chemical Society · doi:10.1021/ja0495213 · Cited by 83 · see citing works
Aptamers: a new class of oligonucleotides in the drug discovery pipeline?
Dausse, E., Gomes, S. D. R., & Toulmé, J. (2009) · Current Opinion in Pharmacology · doi:10.1016/j.coph.2009.07.006 · Cited by 81 · see citing works
Isolating Aptamers Using Capillary Electrophoresis–SELEX (CE–SELEX)
Mosing, R. K., & Bowser, M. T. (2009) · Methods in molecular biology · doi:10.1007/978-1-59745-557-2_3 · Cited by 76 · see citing works
Size, constant sequences, and optimal selection
LEGIEWICZ, M., LOZUPONE, C., KNIGHT, R., & YARUS, M. (2005) · RNA · doi:10.1261/rna.2161305 · Cited by 69 · see citing works
Visualization of Single Multivalent Receptor–Ligand Complexes by Transmission Electron Microscopy
Gestwicki, J. E., Strong, L. E., & Kiessling, L. L. (2000) · Angewandte Chemie International Edition · doi:10.1002/1521-3773(20001215)39:24 · Cited by 64 · see citing works
A computational proposal for designing structured RNA pools for in vitro selection of RNAs
Kim, N., Gan, H. H., & Tamar Schlick, A. (2007) · RNA · doi:10.1261/rna.374907 · Cited by 53 · see citing works
Analyzing partially randomized nucleic acid pools: straight dope on doping
Knight, R. (2003) · Nucleic Acids Research · doi:10.1093/nar/gng030 · Cited by 48 · see citing works
Combinatorial minimization and secondary structure determination of a nucleotide synthase ribozyme
CHAPPLE, K. E., Bartel, D. P., & Unrau, P. J. (2003) · RNA · doi:10.1261/rna.5500603 · Cited by 35 · see citing works
A Deoxyribozyme, Sero1C, Uses Light and Serotonin to Repair Diverse Pyrimidine Dimers in DNA
Thorne, R. E., Chinnapen, D. J. ‐., Sekhon, G. S., & Sen, D. (2009) · Journal of Molecular Biology · doi:10.1016/j.jmb.2009.02.064 · Cited by 24 · see citing works
The adenosine wedge: A new structural motif in ribosomal RNA
Gagnon, M. G., & Steinberg, S. V. (2009) · RNA · doi:10.1261/rna.1550310 · Cited by 14 · see citing works
Combinatorial library diversity: probability assessment of library populations
Ward, B. (1998) · Nucleic Acids Research · doi:10.1093/nar/26.4.879 · Cited by 13 · see citing works
Flagged first, then by citations
Research works printed but not linked: 2
- O’Connell D.; Koenig A.; Jennings S.; Hicke B.; Han H. L.; Fitzwater T.; Chang Y. F.; Varki N.; Parma D.; Varki A. Proc. Natl. Acad. Sci. U.S.A. 1996, 93, 5883–5887. 8650187 PMC39156
- Legiewicz M.; Lozupone C.; Knight R.; Yarus M. RNA 2005, 11, 1701–1709. 16177137 PMC1370856
Cited by
Sorted by citations
Prebiotically plausible mechanisms increase compositional diversity of nucleic acid sequences
Derr, J., Manapat, M. L., Rajamani, S., Leu, K., Xulvi-Brunet, R., Joseph, I., Nowak, M. A., & Chen, I. A. (2012) · Nucleic Acids Research · doi:10.1093/nar/gks065 · Cited by 74 · see citing works
- Authors
- Ruff, K. M., Snyder, T. M., & Liu, D. R.
- Affiliations
- Howard Hughes Medical Institute (US)
- Corresponding author
- Liu, David R.
- Venue
- Journal of the American Chemical Society
- Publisher
- American Chemical Society (ACS)
- Published
- 2010-06-21
- Volume
- 132
- Issue
- 27
- Pages
- 9453-9464
- ISSN
- 0002-7863 (ISSN-L)
- 1520-5126
- PMC
- PMC2898215
- OpenAlex
- W1974116115
- Cited by
- 86
- References
- 42
- Citations by year
- 2026: 7 · 2025: 4 · 2024: 9 · 2023: 5 · 2022: 5 · 2021: 6 · 2020: 1 · 2019: 5 · 2018: 6 · 2017: 4 · 2016: 8 · 2015: 4 · 2014: 5 · 2013: 5 · 2012: 8
- FWCI
- 2.21
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of the American Chemical Society (publishedVersion, other-oa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- Funders
- Howard Hughes Medical Institute
- National Institute of General Medical Sciences (R01GM065400)
- Topics
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA and Nucleic Acid Chemistry
- Keywords
- aptamers, secondary structure, protein binding, in vitro selection, stem-loop structure, library design, binding motifs, folding energy
- MeSH terms
- Nucleic Acid Conformation, Protein Binding, Gene Library, Aptamers, Nucleotide
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
