Structural studies of sugars in solutions are challenging for most of the traditional analytical techniques.
Raman and Raman optical activity (ROA) spectroscopies were found extremely convenient
for this purpose. However, Raman and ROA spectra of saccharides are challenging to
interpret and model due to the saccharides’ flexibility and polarity. In this study, we present an
optimized computational protocol that enables the simulation of the spectra efficiently. Our protocol,
which results in an excellent agreement with experiments, combines molecular dynamics
and density functional theory calculations. It further uses a smart optimization procedure and a
novel adaptable scaling function. The numerical stability and accuracy of individual computational
steps are evaluated by comparing simulated and experimental spectra of D-glucose, D-glucuronic
acid, N-acetyl-D-glucosamine, methyl β-D-glucopyranoside, methyl β-D-glucuronide, and methyl
β-N-acetyl-D-glucosaminide. Overall, our Raman and ROA simulation protocol allows to routinely
and reliably calculate the spectra of small saccharides and opens the door to advanced applications,
such as complete 3-dimensional structural determination by direct interpretation of the
experimental spectra.