The role of enhanced aromatic π-electron donating aptitude of the tyrosyl sidechain with respect to that of phenylalanyl in intramolecular interactions

An exhaustive ab initio and DFT search for energetically stable conformers from the topologically possible set was undertaken on the N-acetyl-phenylalanyl-N-methylamide and N-acetyl-tyrosyl-N-methylamide systems. The geometries of all 81 phenylalanyl and 162 tyrosyl possible rotamers, described under the rules outlined by Multi-Dimensional Conformational Analysis (MDCA), were attempted at each of the RHF/3-21G, RHF/6-31G(d) and B3LYP/6-31G(d) levels of theory. A total of 32 and 66 stable conformational minima were found for the phenylalanyl and tyrosyl amino acid diamides, respectively, at the B3LYP/6-31G(d) level. From the tyrosyl set, 33 unique conformers emerge when the orientation of the A_i ³ dihedral angle (p-OH orientation) is disregarded. A total of 31 conformers were common to both sets and showed nearly identical geometries. The comparison of the optimized DFT geometries of the two systems showed near by perfect linear fits with R² values of 0.9997, 0.9994, 0.9997, and 0.9996 for the φ_i, ψ_i, A_i ¹, and A_i ² dihedral angles, respectively. Relative energies of the matching 31 conformers also fitted to a linear plot with an R² value of 0.9985. The geometric centroid of the aromatic ring in the sidechain of both systems was found to be within 4.1 Å of the H and O atoms of the peptide groups, in 21 and 2 of the conformers, respectively. None of the non-matching conformers showed any such interaction distance ≤4.1 Å.