Quantitative Prediction of Exchangeable Proton Chemical Shifts

Abstract

Accurately predicting NMR chemical shifts of exchangeable protons in solution remains challenging because of the combined influence of solute–solvent interactions and molecular dynamics. We introduce a framework that integrates machine-learning molecular dynamics (ML-MD) with the ShiftML3 machine-learning shielding model for rapid and accurate prediction of NMR spectra in solvated molecules. Although originally developed for solids, ShiftML3 effectively captures intermolecular contributions to shielding in solution. We validate the method across a range of chemically diverse systems, including water in organic solvents, solvated alcohols, hydrogen-bonded nucleobases, glucose anomers, and alkylated acetamides. The ML-MD + ShiftML3 framework reproduces experimentally observed chemical shifts of exchangeable protons with near-quantitative accuracy, resolving subtle hydrogen-bonding and conformational effects that implicit-solvent DFT fails to capture. These results establish ML-MD + ShiftML3 as a transferable and computationally efficient way of incorporating solvation and dynamics into NMR spectroscopy, enabling realistic chemical shift predictions for flexible, hydrogen-bonded, and complex molecular systems. The authors develop a framework integrating machine-learning molecular dynamics with the ShiftML3 machine-learning shielding mode to accurately predict NMR chemical shifts of exchangeable protons in solution, outperforming DFT approaches in capturing solvation effects.