Real-Space Spectral Determination of Short Single-Stranded DNA Sequence Structures

J Am Chem Soc. 2024 Nov 27. doi: 10.1021/jacs.4c12393. Online ahead of print.

Abstract

Resolving the sequence and structure of flexible biomolecules such as DNA is crucial to understanding their biological mechanisms and functions. Traditional structural biology methods remain challenging for the analysis of small and disordered biomolecules, especially those that are difficult to label or crystallize. Recent development of single-molecule tip-enhanced Raman spectroscopy (TERS) offers a label-free approach to identifying nucleobases in a single DNA chain. However, a clear demonstration of sequencing both spatially and spectrally at single-base resolution is still elusive due to the challenges caused by weak Raman signals and the flexibility of DNA molecules. Here, we report a proof-of-principle demonstration to this end, spectrally resolving in real space individual nucleobases and their sequence structures within a short, single-stranded DNA molecule artificially designed. This breakthrough is achieved through the development of subnanometer-resolved low-temperature TERS methodology for such thermally unstable flexible biomolecules. Further TERS mapping over individual nucleobases provides additional structural information about the molecular configurations and even the locations of functional groups, offering a way to track modification types and binding sites in biomolecules.