Probing the environmental sensitivity of thymine CO vibrations through infrared spectra simulations

Infrared spectroscopy is widely used to probe the structural organization of biologically relevant molecules, including peptides, proteins, and nucleic acids. The latter show significant structural diversity, and specific infrared bands provide insights into their conformational ensembles. Among DNA/RNA infrared bands, the CO stretching modes are especially useful, as they are sensitive to the distinct structural arrangements within nucleic acids. However, the relationship between different spectral lineshapes and specific structural features is often non-trivial, especially in highly flexible systems such as single-stranded DNA. In this work, we propose a hybrid quantum-classical computational approach based on the perturbed matrix method for calculating infrared bands in nucleic acids. This approach, previously applied to calculate CO stretching modes in peptides and proteins, is applied here for the first time to DNA. Specifically, using molecular dynamics simulations combined with density functional theory (B3LYP) calculations, we calculate the spectrum arising from the two CO stretching modes of the thymine base, both in water and deuterated water, with a specific focus on the sensitivity of the spectral lineshape to the systems' conformational ensemble. We compute the spectra for 1-methylthymine, thymidine 5'-monophosphate, and a single-stranded oligomer composed of ten thymine bases, and critically compare them to their corresponding experimental signals. Our results indicate that the difference in the relative intensity of the two bands experimentally observed between the spectrum of a single solvated base and that of the oligomer, also captured in the calculated spectra, results from stacking and hydrogen bonding interactions among the bases.