Modeling pH-Dependent NMR Chemical Shift Perturbations in Peptides

Abstract

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 ¼ 0.85, 0.99, and 0.98 for 13 C, 15 N, and 1 H, respectively). Broadly, we provide the groundwork for incorporating pH effects into empirical and semiempirical chemical shift predictors.

Investigation of the influence of pH on the properties and morphology of gelatin hydrogels

“…The upfield shifting is consistent with the findings from the molecular simulations of Artikis and Brooks 47 and the experiments of Platzer et al, 50 where they observed chemical shift perturbations of the δand εamino groups of lysine due to changes in the protonation state.…”

“…Changes in ionization cause alterations in the electronic environment around the atomic nuclei and result in different extents of shielding, causing chemical shifts to be perturbed from typical values. Chemical shift perturbations can occur through site‐specific changes in ionization or through electrostatic interactions that alter the electrostatic field around a nucleus 47–50 . 1D 1 H, 13 C‐{ 1 H} and 2D [ 1 H, 13 C] HSQC NMR spectroscopy data were used to identify the functional groups responsible for the specific NMR peaks observed and were tracked across the pH range of 2–12.…”

“…Chemical shift perturbations can occur through site-specific changes in ionization or through electrostatic interactions that alter the electrostatic field around a nucleus. [47][48][49][50] 1D 1 H, 13 C-{ 1 H} and 2D [ 1 H, 13 C] HSQC NMR spectroscopy data were used to identify the functional groups responsible for the specific NMR peaks observed and were tracked across the pH range of 2-12. An annotated 1D 1 H NMR spectrum is shown in Figure 11, where the peak assignment is based on an NMR study by Rodin and Izmailova.…”

“…As the exchange rate is increased the peaks broaden and begin to coalesce, forming one broad encompassing peak, resulting in the loss of detailed spectral information. 47,[52][53][54] In addition to chemical exchange, the solvent suppression method used can also contribute to diminished peak intensity. Presaturation applies a low power (weak irradiation), continuous pulse to the sample at the solvent resonance for a long period of time (typically 2 s) before the pulse sequence is initiated.…”

Impact of solvent interactions on1H and13C chemical shifts investigated using DFT and a reference dataset recorded in CDCl3and CCl4

“…via hydrogen bonds), which are not trivial to account for in DFT calculations. [15][16][17] Also vibrational contributions to the chemical shift are usually neglected.…”