How reliable could economic Hartree–Fock computations be in studying large, folded peptides? A comparative HF and DFT case study on N- and C-protected aspartic acid

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In this study, potential energy hypersurfaces have been generated and analyzed for each of the nine possible backbone (BB) conformations for both the endo and exo forms of N-acetyl- l-aspartic acid N′-methylamide. Ab initio calculations were carried out at RHF/3-21G, RHF/6-31G(d), and B3LYP/6-31G(d) levels for all backbone conformations. The relative energies, as well as stabilization energies exerted by the sidechain (SC) on the backbone, were calculated for all stable conformers. All sidechain–sidechain (HO⋯OC), backbone–backbone (N–H⋯OC), and sidechain–backbone (N–H⋯OC; N–H⋯OH) hydrogen bond interactions were analyzed. The appearance of the traditionally absent α L and ε L conformers may be recognized as special geometric orientation which the aspartyl residue manifests during peptide folding or ligand docking in a receptor that contains aspartic acids in its ligand recognition sites. At all three levels of theory, there exists a trend between the hydrogen bond distance and ring size. In addition, strikingly high correlations between the torsional angles ( R 2=0.9937 for RHF/6-31G(d) versus RHF/3-21G; R 2=0.9967 for B3LYP/6-31G(d) versus RHF/6-31G(d); R 2=0.9914 for B3LYP/6-31G(d) versus RHF/3-21G) and between the Δ E values in kcal/mol ( R 2=0.9424 for RHF/6-31G(d) versus RHF/3-21G; R 2=0.9108 for B3LYP/6-31G(d) versus RHF/6-31G(d); R 2=0.9434 B3LYP/6-31G(d) versus RHF/3-21G) found at the different ab initio levels suggest that calculations carried out at the lower levels (i.e. at RHF/3-21G) are still significant.