RNA 2018: The 23rd Annual Meeting of the RNA Society

Detection of Ligand-Induced Conformational Changes in Oligonucleotides by Second- Harmonic Generation

Margaret Butko, Gabriel Mercado, Noreen Rizvi, Elliott Nickbarg, Hai-Young Kim, Mark McCoy, Thierry Fischmann, Corey Strickland
1Biodesy, Inc., South San Francisco, CA, USA; 2Merck & Co., Boston, MA, USA; 3Merck & Co., Kenilworth, NJ, USA; 4Siemens Healthineers, Tarrytown, NY, USA

RNA and DNA structural elements play an important role in a variety of biological processes, which make them an appealing target for drug discovery. However, traditional protein higher order structural techniques often face challenges when applied to RNA and DNA molecules. Furthermore, these structural techniques are laborious and not amenable to the throughput needed in drug discovery. Moreover, binding techniques capable of higher throughput often do not resolve functional structural elements. In this study, second-harmonic generation (SHG) technology1was adapted to study RNA and DNA oligonucleotide conformational changes associated with ligand binding. The technique was applied to three distinct RNA/DNA structural classes, including RNA hairpins, G-quartets, and riboswitches, all of which are known to undergo conformational changes upon binding either protein or small molecule ligands.2,3In all three cases, SHG was able to resolve conformational changes in these oligonucleotides sensitively and specifically, in solution and in real time, using nanogram amounts of material. Furthermore, these changes were distinct from conformational changes associated with known nonspecific binders This work demonstrates the broad potential of SHG for studying oligonucleotides and their conformational changes upon interaction with ligands. As SHG offers a powerful, high-throughput screening approach, our results here also open an important new avenue for identifying novel chemical probes or sequence-targeted drugs that disrupt or modulate DNA or RNA structure and function.

1 Moree, B. et al.Biophys J 109, 806-815, doi:10.1016/j.bpj.2015.07.016 (2015).
2 Butko, M. T., Moree, B., Mortensen, R. B. & Salafsky, J. Anal Chem 88, 10482-10489, doi:10.1021/acs.

analchem.6b02498 (2016).
3 Rizvi, N. F. et al. ACS Chem Biol, doi:10.1021/acschembio.7b01013 (2018).

Biodesy Delta System Enables Researchers to Discover Novel Mechanism Involved in Infectious Disease

Nature Communications publication highlights new applications for highly-sensitive SHG technology SOUTH SAN FRANCISCO, Calif. – Nov. 20, 2017 – Biodesy, Inc., a leader in next-generation technologies measuring structure and structural changes at the molecular level, today announced that its Delta ® System was used to discover a novel mechanism involved in the earliest steps of viral infection. The collaborative study

Biodesy article cited as one of the most popular in 2015

Biodesy’s article, “Protein Conformational Changes Are Detected and Resolved Site Specifically by Second-Harmonic Generation” published in Biophysical Journal was announced as one of the most popular articles in the journal in 2015 at the Biophysical Society meeting.


The New York Academy of Sciences: Thinking Outside the ATP Box: New Ways to Target Kinases for Therapeutics

May 22, 2018 The New York Academy of Sciences, 7 World Trade Center, 250 Greenwich St Fl 40, New York

Please join us at the NYAS on May 22nd for our poster presentation:

Discrimination of kinase conformational states upon inhibitor binding by second harmonic generation

Where we show how SHG can be used to discriminate between conformational states of two full-length kinases and a pseudokinase upon binding to well-characterized tool compounds.

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