The Role of Small-Angle X-Ray Scattering and Molecular Simulations in 3D Structure Elucidation of a DNA Aptamer Against Lung Cancer
Morozov, D., Mironov, V., Moryachkov, R. V., Shchugoreva, I. A., Artyushenko, P. V., Zamay, G. S., Kolovskaya, O. S., Zamay, T. N., Krat, A. V., Molodenskiy, D. S., Zabluda, V. N., Veprintsev, D. V., Sokolov, A. E., Zukov, R. A., Berezovski, M. V., Tomilin, F. N., Fedorov, D. G., Alexeev, Y., & Kichkailo, A. S. (2021). The Role of Small-Angle X-Ray Scattering and Molecular Simulations in 3D Structure Elucidation of a DNA Aptamer Against Lung Cancer. Molecular Therapy Nucleic Acids, 25, 316-327. https://doi.org/10.1016/j.omtn.2021.07.015
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Molecular Therapy Nucleic AcidsAuthors
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2021Copyright
© 2021 the Authors
Aptamers are short, single-stranded DNA or RNA oligonucleotide molecules that function as synthetic analogs of antibodies and bind to a target molecule with high specificity. Aptamer affinity entirely depends on its tertiary structure and charge distribution. Therefore, length and structure optimization are essential for increasing aptamer specificity and affinity. Here we present a general optimization procedure for finding most populated atomistic structures of DNA aptamers. Based on the existed aptamer LC-18 for lung adenocarcinoma, a new truncated aptamer LC-18t was developed. A three-dimensional shape of LC-18t was reported based on small-angle X-ray scattering (SAXS) experiments and molecular modeling by fragment molecular orbital or molecular dynamic methods. Molecular simulations revealed an ensemble of possible aptamer conformations in solution that were in close agreement with measured SAXS data. The truncated aptamer LC-18t had stronger binding to cancerous cells in lung tumor tissues and shared the binding site with the original larger aptamer. The suggested approach reveals 3D shapes of aptamers and helps in designing better affinity probes.
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Research infrastructures, H2020
The content of the publication reflects only the author’s view. The funder is not responsible for any use that may be made of the information it contains.
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The study was supported by a grant from the Russian Science Foundation (project No. 21-73- 20240) for A.S.K. D.G.F. acknowledges financial support by JSPS KAKENHI, grant number 19H02682. D.S.M. acknowledges financial support by BMBF, grant number 16QK10A (SAS- BSOFT). Yuri’s work at Argonne National Laboratory was supported by the U.S. Journal Pre-proof Department of Energy, Office of Science, under contract DE-AC02- 06CH11357. D.M. received funding as a part of BioExcel CoE (www.bioexcel.eu), a project funded by the European Union contracts H2020-INFRAEDI-02-2018-823830 and H2020- EINFRA-2015- 1-675728. V.M. thanks Russian Foundation for Basic Research (project number 19-03- 00043) for funding. ...License
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