Evaluating electronic structure methods for accurate calculation of 19F chemical shifts in fluorinated amino acids

The ability of electronic structure methods (11 density functionals, HF, and MP2 calculations; two basis sets and two solvation models) to accurately calculate the 19F chemical shifts of 31 structures of fluorinated amino acids and analogues with known experimental 19F NMR spectra has been evaluated. For this task, BHandHLYP, ωB97X, and Hartree–Fock with scaling factors (provided within) are most accurate. Additionally, the accuracy of methods to calculate relative changes in fluorine shielding across 23 sets of structural variants, such as zwitterionic amino acids versus side chains only, was also determined. This latter criterion may be a better indicator of reliable methods for the ultimate goal of assigning and interpreting chemical shifts of fluorinated amino acids in proteins. It was found that MP2 and M062X calculations most accurately assess changes in shielding among analogues. These results serve as a guide for computational developments to calculate 19F chemical shifts in biomolecular environments. © 2017 Wiley Periodicals, Inc. Fluorinated amino acids are used to label proteins for studies of structure, dynamics, and function. Interpreting and assigning the chemical shifts in the resulting fluorine NMR spectra of fluoro‐labeled proteins is a goal of computational chemists. This article provides key information toward this aim, by evaluating the ability of numerous electronic structure methods to calculate fluorine chemical shifts of amino acids and analogues. Methods are evaluated in terms of lowest deviation from experimental values.