Modeling pH-Dependent NMR Chemical Shift Perturbations in Peptides.

Modeling the pH dependence of protein and peptide chemical shifts outside the range of physiological values (6.5-7) is key to understanding structure-function relationships of these systems. These capabilities are largely not available in current chemical shift prediction software. In this study, we utilize a combination of molecular dynamics and quantum mechanics to investigate the through-space and through-bond contributions of protonation-dependent chemical shift perturbations (CSPs) in model tripeptides. By altering the protonation state of the titratable group in the tripeptides, we observe a notable difference in the conformational ensembles and attendantly compute significant CSPs for all nuclei near the site of protonation. We thus demonstrate the ability to recapitulate experimental pH-dependent CSPs with good agreement (R = 0.85, 0.99, and 0.98 for 13C, 15N, and 1H, respectively). Broadly, we provide the groundwork for incorporating pH effects into empirical and semiempirical chemical shift predictors.