Assessing the Performance of Popular Quantum Mechanics and Molecular Mechanics Methods and Revealing the Sequence-Dependent Energetic Features Using 100 Tetrapeptide Models

A reasonable description of the conformation energies of each of the amino acids is crucial for modeling protein structures and dynamics. We here used 20 tetrapeptides (ACE-ALA-X-ALA-NME, X = one of 20 amino acids) in 5 conformations (right-handed helix (alpha(R)), left-handed helix (alpha(L)), beta-sheet (beta), antiparallel beta-sheet (beta(a)), and polyproline II (PPII)) as structural models to investigate the relative conformation energies at the MP2/cc-pVTZ//B3LYP/6-31G** level. The results indicate that the energetic pattern (the order and the energy gap) of the five conformations bears certain resemblances among the amino acids in the same class but is quite different among the amino acids in the different classes (e.g., hydrophobic, aromatic, polar and charged classes). The MP2 energies are then used to statistically evaluate the overall performance of various methods including density functional methods (M05-2X, PBE, and B3LYP), semiempirical methods (AM1, PM3, and PM3MM), empirical polarizable force fields (AMOEBA and AMBER), additive force fields (AMBER, CHARMM, GROMOS, OPLS-AA), and united-atom force fields (AMBERUA and GROMOS). In general, M05-2X obviously outperforms PBE and B3LYP. The semiempirical methods are not able to reach the accuracy as expected. Some of the additive force fields are more accurate than the semiempirical methods. The AMOEBA polarizable force field has accuracy comparable with (or better than) the B3LYP and PBE methods. AMBER99, OPLS-AA, CHARMM27 (excluding (alpha(L)), and AMBERUA (excluding (alpha(L)) reach reasonable accuracy. However, further improvements, in particular on left-handed helical (alpha(L)) and some residues such as Pro, Asp, and Glu, are necessary.