NA-CDQuant: Quantitative spectral analysis of nucleic acid structure by circular dichroism spectroscopy
7 affiliations
- 1Laboratoire Léon Brillouin, UMR12 Commissariat à l'Énergie Atomique et aux énergies alternatives CNRS, Saclay, Gif-sur-Yvette 91191, France.
- 2Synchrotron SOLEIL, DISCO beamline, L'Orme des Merisiers, Gif-sur-Yvette Saint Aubin BP48, 91192, France.
- 3Biochemistry and Biophysics mRNA Unit, Sanofi, mRNA Center of Excellence, Analytical Sciences, Marcy l'Etoile 69280, France.
- 4ISA, Department of Physics and Astronomy, Aarhus University, Aarhus 8000, Denmark.
- 5Department of Chemistry, Biology and Health Sciences, South Dakota School of Mines and Technology, Rapid City, SD 57701.
- 6Sanofi, Biophysics, Imaging, Particles & Process Analysis Unit Neuville, Biochemistry & Biophysics Neuville, Global Analytical Sciences, Neuville Sur Saône 69350, France.
- 7Université Paris Cité, Unité de Formations et de Recherche des Sciences du Vivant, Paris 75006, France.
Abstract
Understanding the structural conformation and dynamics of nucleic acids in solution is critical for the development of nucleic acid therapeutics involving antisense or mRNA therapies, where controlling stability, efficacy, and manufacturability are important. Circular dichroism (CD) spectroscopy allows rapid and nondestructive solution analysis of the spatial arrangements of nucleic acids. While widely used to analyze protein structure, the potential of CD for DNA- and RNA-based pharmaceutical applications has remained largely unrealized because nucleic acid spectra are complex and difficult to interpret quantitatively. We introduce herein a framework (NA-CDQuant) that transforms CD from a qualitative fingerprinting method into a quantitative tool for nucleic acid structure prediction by combining spectral deconvolution with a rigorously curated synchrotron radiation circular dichroism reference library comprising 18 structurally defined conformational families. This systematic classification overcomes long-standing challenges posed by spectral overlap and structural polymorphism, enabling estimation of the fractional composition of coexisting conformations during real-time monitoring of structural transitions in solution. NA-CDQuant provides mechanistic insight into subtle conformational redistributions that may affect molecular recognition and functional performance assisting pharmaceutical development and medical application by facilitating formulation optimization, stability assessment, quality control, and regulatory support of nucleic acid-based therapeutics.
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BibTeX
@article{mosca2026nacdquant,
title = {{NA-CDQuant: Quantitative spectral analysis of nucleic acid structure by circular dichroism spectroscopy}},
author = {Kevin Mosca and Søren Vrønning Hoffmann and Nykola C Jones and Richard R Sinden and Frank Wien and Sergio Marco and Véronique Arluison},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
year = {2026},
month = oct,
doi = {10.1073/pnas.2617882123},
url = {https://hal.science/hal-05783475v1},
note = {CC BY},
}
RIS
TY - JOUR
TI - NA-CDQuant: Quantitative spectral analysis of nucleic acid structure by circular dichroism spectroscopy
AU - Kevin Mosca
AU - Søren Vrønning Hoffmann
AU - Nykola C Jones
AU - Richard R Sinden
AU - Frank Wien
AU - Sergio Marco
AU - Véronique Arluison
PY - 2026
DA - 2026/10/06
JO - Proceedings of the National Academy of Sciences of the United States of America
DO - 10.1073/pnas.2617882123
UR - https://hal.science/hal-05783475v1
AB - Understanding the structural conformation and dynamics of nucleic acids in solution is critical for the development of nucleic acid therapeutics involving antisense or mRNA therapies, where controlling stability, efficacy, and manufacturability are important. Circular dichroism (CD) spectroscopy allows rapid and nondestructive solution analysis of the spatial arrangements of nucleic acids. While widely used to analyze protein structure, the potential of CD for DNA- and RNA-based pharmaceutical applications has remained largely unrealized because nucleic acid spectra are complex and difficult to interpret quantitatively. We introduce herein a framework (NA-CDQuant) that transforms CD from a qualitative fingerprinting method into a quantitative tool for nucleic acid structure prediction by combining spectral deconvolution with a rigorously curated synchrotron radiation circular dichroism reference library comprising 18 structurally defined conformational families. This systematic classification overcomes long-standing challenges posed by spectral overlap and structural polymorphism, enabling estimation of the fractional composition of coexisting conformations during real-time monitoring of structural transitions in solution. NA-CDQuant provides mechanistic insight into subtle conformational redistributions that may affect molecular recognition and functional performance assisting pharmaceutical development and medical application by facilitating formulation optimization, stability assessment, quality control, and regulatory support of nucleic acid-based therapeutics.
SN - 0027-8424
SN - 1091-6490
ER -