Which DFT levels of theory are appropriate in predicting the prolyl cis–trans isomerization in solution?

Abstract

The performances of the M06-2X and ωB97X-D functionals with various basis sets as well as the double-hybrid DSD-PBEP86-D3BJ/cc-pVTZ level of theory with the implicit PCM and SMD solvation methods were assessed for the conformational preferences of Ac-Pro-NHMe in chloroform and water. The M06-2X/def2-TZVP//M06-2X/6-31+G(d) and DSD-PBEP86-D3BJ/cc-pVTZ//M06-2X/6-31+G(d) methods with PCM in chloroform and SMD in water exhibited the best performances for these conformational preferences consistent with experimental results in chloroform and water. As a further step in checking the applicability of these DFT methods, we have undertaken a study of the conformational preferences of Ac-Pro-OMe, Ac-X-OMe, and Ac-X-NHMe (X = Pro derivatives) in chloroform and/or water. Almost the same results were obtained at both levels of theory. The order of the distributions of puckerings depending on the trans and cis peptide bonds was different depending on the substitution position, the chirality, and the solvent polarity. The cis populations of the prolyl peptide bond for Ac-X-OMe and Ac-X-NHMe (X = Pro and its derivatives) were well predicted with RMSD < 6% in chloroform and water, compared with the experimental values. In addition, the calculated barriers ΔG^‡_c→t to the cis-to-trans isomerization of the prolyl peptide bond for Ac-Pro-NHMe, Ac-X-OMe (X = Pro, Hyp, Flp, and flp), and Ac-X-NHMe (X = 5-Mep, 5-Tbp, and 5-tbp) in chloroform and/or water were consistent with the experimental values within 1 kcal mol⁻¹. Hence, the M06-2X/def2-TZVP//M06-2X/6-31+G(d) and DSD-PBEP86-D3BJ/cc-pVTZ//M06-2X/6-31+G(d) methods with PCM in chloroform and SMD in water appeared to be appropriate in predicting the conformational preferences and the cis–trans isomerization of the longer peptides containing Pro or Pro derivatives in chloroform and water.