Abstract
The i-motif is a pH-responsive cytosine-rich oligonucleotide sequence that forms, under acidic conditions, a quadruplex structure. This tunable structural switching has made the i-motif a useful platform for designing pH-responsive nanomaterials. Despite the widespread application of i-motif DNA constructs as biomolecular switches, the mechanism of i-motif folding on the atomic scale has yet to be established. We investigate the early folding structural dynamics of i-motif oligonucleotides with laser-pulse-induced pH-jump time-resolved X-ray solution scattering. Following the pH-jump, we observe that the initial random coil ensemble converts into a contracted intermediate state within 113 ns followed by further folding on the 10 ms time scale. We reveal the representative structures of these transient species, hitherto unknown, with molecular dynamics simulations and ensemble fitting. These results pave the way for understanding metastable conformations of i-motif folding and for benchmarking emerging theoretical models for simulating noncanonical nucleic acid structures.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 33743-33752 |
| Number of pages | 10 |
| Journal | Journal of the American Chemical Society |
| Volume | 146 |
| Issue number | 49 |
| DOIs | |
| State | Published - Dec 11 2024 |
Funding
This work was supported by the National Institute of Health (NIH), under contract no. R01-GM115761. A.M.C. and M.B.H. acknowledge support from the NIH/National Institute of General Medical Sciences (NIGMS) sponsored Molecular Biophysics Training Program at Northwestern University (T32GM140995). This material is based upon work supported by the National Science Foundation under Grant DBI- 2032180. S.B.E. was supported in part by the Chicago Cancer Baseball Charities and the H Foundation at the Lurie Cancer Center of Northwestern University. This research used resources of the Advanced Photon Source (APS), a U.S. DOE Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory under contract no. DE-AC02-06CH11357. The use of BioCARS was also supported by the NIH-NIGMS under grant number R24GM111072. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Time-resolved setup at Sector 14 was funded in part through a collaboration with Philip Anfinrud (NIH/NIDDK). Optical equipment used for UV beam delivery at BioCARS was purchased with support from the Fraser lab at the University of California San Francisco. Portions of this work were performed at the DuPont-Northwestern-Dow Collaborative Access Team (DND-CAT) located at Sector 5 of the APS. DND-CAT is supported by Northwestern University, The Dow Chemical Company, and DuPont de Nemours, Inc.
ASJC Scopus subject areas
- Catalysis
- General Chemistry
- Biochemistry
- Colloid and Surface Chemistry