Sequence‐Encoded Frustration Directs the Formation of Abridged G‐Quadruplex Architectures

Frustration—competing interactions that cannot be simultaneously optimized—shapes energy landscapes in proteins and softmatter, but has rarely been exploited as a programmable design principle in nucleic acids. Here we demonstrate that sequence-encoded frustration programmes DNA G-quadruplex folding, yielding stable “abridged” architectures with fewer guanine tetradsthan the sequence would nominally permit. Using an integrated structural, spectroscopic, thermodynamic, and computationalapproach, we map a frustration-biased folding landscape featuring a thermodynamically stabilized G-triplex intermediate, whoseidentity we assign via TD-DFT computed electronic circular dichroism spectra, and resolve the dominant unfolding pathway atatomic resolution. These results demonstrate programmable frustration as a predictive design principle for controlling nucleicacid topology and dynamics, offering new strategies for engineering functional DNA-based systems and for interpreting genomicG-quadruplex plasticity.