Toward Reliable Conformational Energies of Amino Acids and Dipeptides─The DipCONFS Benchmark and DipCONL Datasets

Abstract

Simulating peptides and proteins is becoming increasingly important, leading to a growing need for efficient computational methods. These are typically semiempirical quantum mechanical (SQM) methods, force fields (FFs), or machine-learned interatomic potentials (MLIPs), all of which require a large amount of accurate data for robust training and evaluation. To assess potential reference methods and complement the available data, we introduce two sets, DipCONFL and DipCONFS, which cover large parts of the conformational space of 17 amino acids and their 289 possible dipeptides in aqueous solution. The conformers were selected from the exhaustive PeptideCS dataset by Andris et al. [ J. Phys. Chem. B 2022, 126, 5949-5958]. The structures, originally generated with GFN2-xTB, were reoptimized using the accurate r²SCAN-3c density functional theory (DFT) composite method including the implicit CPCM water solvation model. The DipCONFS benchmark set contains 918 conformers and is one of the largest sets with highly accurate coupled cluster conformational energies so far. It is employed to evaluate various DFT and wave function theory (WFT) methods, especially regarding whether they are accurate enough to be used as reliable reference methods for larger datasets intended for training and testing more approximated SQM, FF, and MLIP methods. The results reveal that the originally provided BP86-D3(BJ)/DGauss-DZVP conformational energies are not sufficiently accurate. Among the DFT methods tested as an alternative reference level, the revDSD-PBEP86-D4 double hybrid performs best with a mean absolute error (MAD) of 0.2 kcal mol^-1 compared with the PNO-LCCSD(T)-F12b reference. The very efficient r²SCAN-3c composite method also shows excellent results, with an MAD of 0.3 kcal mol^-1, similar to the best-tested hybrid ωB97M-D4. With these findings, we compiled the large DipCONFL set, which includes over 29,000 realistic conformers in solution with reasonably accurate r²SCAN-3c reference conformational energies, gradients, and further properties potentially relevant for training MLIP methods. This set, also in comparison to DipCONFS, is used to assess the performance of various SQM, FF, and MLIP methods robustly and can complement training sets for those.