Comparison of Energy-Minimized Structures of [PdII(N-methyliminodiacetate)] Complexes of X1-His-X3-His-His Peptides as an Analysis of Steric and Specific Interactions with Synthetic Binding Tags for IMAC Separations

[PdII(mida)(peptide)] complexes for the series of peptides of sequence X1-His-X3-HisHis were studied by molecular mechanics methods using Spartan, MMFF94, and SYBYL programs with X1 = X3 = glycine (G), phenylalanine (F), tyrosine (Y), tryptophan (W), and with X1 = glycine (G) and X3 = proline (P). For comparison purposes, data were also obtained for the Ser-Pro-His-His-Gly (SPHHG) and the (His)5 peptides.The latter two peptides and GHPHH are tags in current use for IMAC separations. These provide calibration points as to the binding affinities that have been determined for the entire series. The energies of the complexes, as an average trend found from the composite behavior of the three methods, were found to be SPHHG (205* kcal/mol) (most stable; * are values obtained by MMFF94 methods) < HH#HH#H# (222*; where # implies the site of attachment to match the other X1-HisX3-His-His peptides) < YHYHH (249*) < GHGHH (265*) < WHWHH (284*) ~~ GHPHH (286*) < FHFHH (311*) (least stable), implying that FHFHH might be a useful chromatographic tag for IMAC protein separations that would elute more readily than GHPHH from IMAC sites that are of square-planar structure, such as CuII(idasupported) IMAC columns. Specific H-bonded interactions are observed between the tyrosine X1 and pendant carboxylates and between X3 and the N-terminal amine of [Pd(mida)(YHYHH)]. Face-to-n-face ring stacking occurs between phenylalanine X1 and X3 units in [Pd(mida)(FHFHH)], whereas edge C—H to n H-bonding or n stacking occurs between the X1 and X3 tryptophans of [Pd(mida)(WHWHH)]. Two energy minima were found with tryptophan. The more stable form has the aromatic rings more parallel, similar to the stacked form of phenylalanine, rather than the edge C—H to n H-bonding, and virtually the same overall energy as for [Pd(mida)(GHPHH)]. The "perpendicular" structure was found as an initial local energy minimum, but additional MMFF94 calculations found the n -stacked arrangement at energy ca. 39 kcal/mol lower than that of the nearly "perpendicular" arrangement of the tryptophan rings, a composite effect of relaxation of the peptide, together with differences in stabilities imparted by the differing geometries. The use of the terms n-stacked " and "perpendicular" forms represent the limiting cases available to the tryptophan side chain groups. A twist of about 15° to 20° in dihedral angle is all that is necessary to change between structures that are nearly described as one form or the other.