Metalation of Glycylglycine: An Experimental Study Performed in Tandem with Theoretical Calculations

Abstract

Interactions of the Ni 2+ , Cu 2+ , and Zn 2+ ions with the simplest dipeptide glycylglycine (GlyGly) are explored using various experimental and computational techniques. Solid and aqueous phase syntheses of the metalated GlyGly complexes (by solid-state grinding and by coprecipitation respectively) lead to the same products, as confirmed by physicochemical and spectral properties which indicate metal-coordination through the −NH 2 and −CO 2 − groups of the dipeptide. Phase-diagram and kinetic studies of the solid-phase reaction between GlyGly and copper acetate suggest that complexation occurs in 1:2 (metal/ligand) stoichiometry via a facile kinetic pathway (a barrier of only 22.22 kJ/mol). The right-handed α-helical conformer of GlyGly is considered in DFT modeling studies in gas and aqueous phases elucidating the effects of metalation and solvation upon structural, electronic, and vibrational properties of the complexes. The complexes are found to follow the stability order Cu 2+ > Ni 2+ > Zn 2+ corroborating the Irving-Williams series. The Ni(GlyGly) 2 complex is predicted to exist in its low-spin state. Hydration effects on structural aspects of the complexes are also investigated computationally. The BHandHLYP/6-311++G(d,p) level describes the Cu(GlyGly) 2 complex more efficiently than the B3LYP/6-311++G(d,p) level (which, however, better predicts the vibrational spectra of the systems). Absorption titration experiments with calf thymus DNA together with in silico docking and molecular mechanical studies reveal that these metal−dipeptide complexes are DNA minor-groove binders primarily through Hbonding interactions, yielding a DNA-binding affinity order of Ni 2+ > Zn 2+ > Cu 2+ .

Physicochemical properties of the ternary complexes of Pt(ii) with uracil and small peptide moieties: an experimental and computational study

“…As evident from Table S3 (ESI †), the appearance of n(N 3 -H), n(C 4 QO) and n(C 4 -N 3 ) vibrational modes of the amide moieties of the dipeptides and their mixed ligand Pt(II) complexes in the ranges of 3428-3449 cm À1 , 1687-1718 cm À1 and 1228-1237 cm À1 , respectively, in both solid and solvent phases suggests that the dipeptides do not interact with Pt(II) ions via their CONH groups. 43,46 On the other hand, the asymmetric and symmetric n(N-H) stretching modes of the three dipeptides (observed at 3251-3230 and 3110-3067 cm À1 respectively) are blue-shifted (3259-3232 and 3176-3116 cm À1 respectively) in their metal complexes. This indicates the deprotonation of the NH 3 + moieties of the free dipeptides and subsequent binding to the Pt(II) ions through the amino nitrogen atoms.…”

“…1) have been well documented in the literature. 42,43 It is known that the C7 eq. However, since there is no existing experimental evidence of C5 as being the most stable conformer of a given dipeptide in the aqueous phase, 42 we opt to design the mixed ligand complexes using the biologically relevant right-handed alpha-helical conformers of the three dipeptides i.e.…”

“…This indicates the deprotonation of the NH 3 + moieties of the free dipeptides and subsequent binding to the Pt(II) ions through the amino nitrogen atoms. 33,43,47 Indication of metal coordination through the -NH 2 functions of the dipeptides is also provided by the fact that the n(C 5 -N 6 ) stretching values of the dipeptides (observed at 1102-1132 cm À1 ) are red-shifted in the spectra of their metal complexes (1093-1127 cm À1 ). The appearance of new strong bands in the range of 473-480 cm À1 in all the three metal complexes, 33,47 which can be assigned to asymmetric n(M-N) stretching frequencies, 48 also confirms that the amino nitrogen atoms of the dipeptides are involved in metal coordination.…”

“…Additionally, it is worth mentioning that the two coordinating -NH 2 groups are positioned trans to each other in the complexes since the symmetric n(M-N) stretching mode of the N-M-N group (MQPt(II)) which usually appears around 400-450 cm À1 is IR inactive. 43,48 Concerning the experimental infrared spectral data on the carboxylate groups of the dipeptides and their metal complexes, the n as (COO À ) modes of the dipeptides appearing at 1603-1626 cm À1 are found to shift toward the higher wave numbers of the frequency scale (up to 1667 cm À1 ), whereas the n s (COO À ) stretches (observed at 1406-1454 cm À1 ) shift to the lower-side in the complexes (1400-1419 cm À1 ). These observations indicate that the dipeptides bind to the metal ions via their carboxylate functions.…”

“…These observations indicate that the dipeptides bind to the metal ions via their carboxylate functions. 33,43,47 Table S3 (ESI †) also gathers the differences (Dd values) between the n as (COO À ) and n s (COO À ) stretches for the dipeptides and the metal complexes which are indicative of the M-O bond strengths and provide evidence that the COO À groups bind to the metal ions in a monodentate fashion. 43,47 The Dd values of the metal complexes ranging from 227 to 249 cm À1 indicate that the M-O bonds possess significant covalent characters.…”