Comparison of energy-minimized structures of [PdII(mida)] complexes of peptide sequences used in immobilized metal ion affinity chromatography protein separations

Molecular mechanics calculations were performed using the mm2, Spartan, mmff94 and sybyl programs to examine the stabilities of complexes of the formulation [PdII(mida)L3] and [PdII(mida)(hexamer peptide)] (mida2−=N-methyliminodiacetate) as influenced by steric factors of the three coordination positions other than the point of attachment to the mida2− ligand. The series of monodentate ligands (L) follows a stability order of lowest energy (most stable) to highest energy (least stable) as follows: (Cl−)3∼(H−)3<(im)2(NH3−nMen)<(im)3<(im)2(NH3)<(NMe3)3<(NHMe2)3<(NH2Me)3<(NH3)3 (im=imidazole, Me=methyl; n=1 to 3). The calculations show that for monodentate ligand sets, the two cis imidazoles plus amine donors set provides the energetically best donor system rather than an all imidazole or all amine set of donors for typical N-donors that are available from peptides. The same ligand set is used by the peptide anchor of sequence Ser–Pro–His–His–Gly–Gly (SPHHGG), which provides the best protein anchor that can be removed in the pH 5 to pH 7 ‘chromatography window’ from CuII(ida)-derivatized columns for immobilized metal ion affinity chromatography (IMAC) protein separations. Also, the L3 series of the present study shows that increasing the substitution around the amine donor enhances the stability through better σ donation in spite of increasing steric interactions. A limited peptide series was also treated by four molecular mechanics procedures. The outcome of the stability order as predicted by the four separate computer methods is more mixed when chelation between the imidazole and amine donors is included in the calculations. The peptides amH6, imH6, amH4G2, imH4G2, GHPHHG, SPHHGG, and G6 were evaluated. The ligand notation amH6 and imH6, etc., implies the situation with the N-terminal donor as the amine and as the histidyl group respectively. The ligand G6 was coordinated as the terminal amine and two deprotonated amido donors. In general, the G6-type coordination provides a low energy situation comparable to the best donor sets of the side chain type of coordination (SPHHGG, amH6, GHPHHG, etc.). The mmff94, sybyl and Spartan calculations produced the energy-minimization order of (most to least stable): G6