Conformational dependence of the intrinsic acidity of the aspartic acid residue sidechain in N-acetyl-l-aspartic acid-N′-methylamide

The sidechain conformational potential energy hypersurfaces (PEHS) for the γL, βL, αL, and αD backbone conformations of N-acetyl-l-aspartate-N′-methylamide were generated. Of the 81 possible conformers initially expected for the aspartate residue, only seven were found after geometric optimizations at the B3LYP/6-31G(d) level of theory. No stable conformers could be located in the δL, εL, γD, δD, and εD backbone conformations. The ‘adiabatic’ deprotonation energies for the endo and exo forms of N-acetyl-l-aspartic acid-N′-methylamide were calculated by comparing their optimized relative energies against those found for the seven stable conformers of N-acetyl-l-aspartate-N′-methylamide. Sidechain conformational PEHSs were also generated for the estimation of ‘vertical’ deprotonation energies for both endo and exo forms of N-acetyl-l-aspartic acid-N′-methylamide. All backbone–sidechain (N–H⋯−O–C) and backbone–backbone (N–H⋯OC) hydrogen bond interactions were analyzed. A total of two backbone–backbone and four backbone–sidechain interactions were found for N-acetyl-l-aspartate-N′-methylamide. The deprotonated sidechain of N-acetyl-l-aspartate-N′-methylamide may allow the aspartyl residue to form strong hydrogen bond interactions (since it is negatively charged) which may be significant in such processes as protein–ligand recognition and ligand binding. As a primary example, the molecular geometry of the aspartyl residue may be important in peptide folding, such as that in the RGD tripeptide.