Terahertz Raman Optical Activity Reveals Emergent Supramolecular Chirality in Mononucleotide G-quadruplexes

Abstract

Raman optical activity (ROA) provides unique chiroptical insights into biomolecular structure but suffers from inherently weak signals. A substantial enhancement in the low-wavenumber/THz region (50-250 cm(-1) /1.5-7.5 THz) of ROA spectra upon the formation of mononucleotide G-quadruplexes (mG4) from guanosine-5-monophosphate (5'rGMP) is reported. Using concentration-dependent Raman and ROA measurements, a nearly 100-fold increase in ROA intensity upon aggregation is identified, with spectral features highly sensitive to cation-mediated structural variations. These effects can be traced to long-range chiral interactions and distinct stacking arrangements within mG4.While strong terahertz Raman optical activity (THz-ROA) signals have previously been observed in globular proteins and α-helical polypeptides, the findings of this study represent the first evidence of this phenomenon in nucleotides, demonstrating that noncovalent self-assembly into supramolecular helices can give rise to intense low-frequency chiroptical responses. This establishes THz-ROA as a powerful background-free tool for studying supramolecular chirality and nucleotide self-assembly, with potential applications in characterizing biologically relevant G-quadruplex structures.