Toward Accurate Conformational Energies of Smaller Peptides and Medium-Sized Macrocycles: MPCONF196 Benchmark Energy Data Set

A carefully selected set of acyclic and cyclic model peptides and several other macrocycles, comprising 13 compounds in total, has been used to calibrate the accuracy of the DFT­(-D3) method for conformational energies, employing BP86, PBE0, PBE, B3LYP, BLYP, TPSS, TPSSh, M06-2X, B97-D, OLYP, revPBE, M06-L, SCAN, revTPSS, BH-LYP, and ωB97X-D3 functionals. Both high- and low-energy conformers, 15 or 16 for each compound adding to 196 in total, denoted as the MPCONF196 data set, were included, and the reference values were obtained by the composite protocol, yielding the CCSD­(T)/​CBS extrapolated energies or their DLPNO-CCSD­(T)/​CBS equivalents in the case of larger systems. The latter was shown to be in near-quantitative (∼0.10–0.15 kcal·mol^–1) agreement with the canonical CCSD­(T), provided the TightPNO setting is used, and, therefore, can be used as the reference for larger systems (likely up to 150–200 atoms) for the problem studied here. At the same time, it was found that many D3-corrected DFT functionals provide results of ∼1 kcal·mol^–1 accuracy, which we consider as quite encouraging. This result implies that DFT-D3 methods can be, for example, safely used in efficient conformational sampling algorithms. Specifically, the DFT-D3/​DZVP-DFT level of calculation seems to be the best trade-off between computational cost and accuracy. Based on the calculated data, we have not found any cheaper variant for the treatment of conformational energies, since the semiempirical methods (including DFTB) provide results of inferior accuracy (errors of 3–5 kcal·mol^–1)