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Pt-based anti-cancer drugs can form complexes with biological ligands other than their intended pharmacological targets. Such complexes are believed to be a major contributor to the reduction of the anti-cancer drugs’ therapeutic potential and can act as potential causes of toxicity. Recently, the cytoplasmic ligand β - alanyl-L-histidine dipeptide (carnosine) was shown to act as a sequestering agent for oxaliplatin (OxPt) inhibiting its cytotoxic action most likely through the formation of complexes that are less cytotoxic than OxPt alone. In this paper, the calculated binding modes and binding energies of protonated carnosine as well as canosine complexes with various biologically relevant metal cations and some common Pt-based anti-cancer drugs both in the gas phase and in solution are presented. Theoretical evidence for the existence of protonated carnosine in a zwitterionic form is offered. Six calculated geometrical arrangements comprising general structural motifs of metal ion-carnosine complexes are presented. In all but one of these six conformers the metal ions were shown to form three bonds to each of the carnosine ligands. These six general binding motifs were found to cover the lowest energy structures of all species investigated here whether in the gas phase or in solution. The data presented increases our knowledge of the interactions of carnosine with different metals, either those naturally found inside the body or those that are up taken via foods, supplements or drugs.

A detailed structural analysis of the complexes resulting from the association of the neutral, mono- and di-anionic forms cytoplasmic thiol containing tripeptide glutathione (GSH) to the post water substituted hydrolysed form of the anti-cancer drug cisplatin, [Pt(NH 3 ) 2 ] 2+ , in the gas phase and in solution is presented. These structures which are formed from a 1:1 molar ratio of the glutathione ligand and the Pt-drug, have been proposed as possible intermediates for several postulated disulfide bridged polymeric species. Ten gas phase structures on the [GSH − H + Pt(NH 3 ) 2 ] + potential energy surface are presented and the coordination of the Pt metal is discussed. The [GSH + Pt(NH 3 ) 2 ] 2+ potential energy surface was also explored and twelve gas phase structures on this surface are presented. In order to describe the complexes examined here in solution, water solvation effects were considered for eight and nine of the most energetically favored structures of the [GSH − H + Pt(NH 3 ) 2 ] + and [GSH + Pt(NH 3 ) 2 ] 2+ potential energy surfaces, respectively. The enthalpy and free energy, based on the most thermodynamically favored conformers of the reactants and products, for the addition reaction [Pt(NH 3 ) 2 ] 2+ + [GSH − H] − → [GSH − H + Pt(NH 3 ) 2 ] + in the gas phase at 298 K were determined to be −331.8 and −314.8 kcal mol −1 , respectively. Similarly, the enthalpy and free energy of the gas phase reaction [Pt(NH 3 ) 2 ] 2+ + GSH → [GSH + Pt(NH 3 ) 2 ] 2+ at 298 K were determined to be −185.0 and −167.4 kcal mol −1 .

Positive mode electrospray mass spectrometry was used to investigate complexes of cysteine and selenocysteine with the metallo-drug Auranofin and the analogous chlorotriethylphosphine gold. Evidence for all the complexes, with the exception of the Auranofin–selenocysteine complex, was obtained. Several fragmentation products were examined and their proposed structures reported. Structural details of many experimentally observed ions including [Auranofin + H] + , [(CH 3 CH 2 ) 3 P–Au–cysteine] + and [(CH 3 CH 2 ) 3 P–Au–methylselenocysteine] + were examined by means of hybrid density functional theory at the B3LYP/DZVP level. Structural information and relative free energies are presented for several isomers of each ion considered.

The complexes of Ag + with the peptides MetGly, ProGly, GlyPro, GlyHis and GlyProAla were investigated using hybrid density functional theory at the B3LYP/DZVP level. The silver ion binding free energies at 298 K to each of these peptides was calculated to be 60.8, 52.0, 54.3, 71.2 and 63.3 kcal mol −1 , respectively. Structural information and relative free energies are presented for several isomers for each of the five complexes. Each of the global minima found for the five complexes is a charge-solvated ion. An important finding is that the Ag + –ProGly is the only complex where a salt bridge structure is energetically favored occurring at 4.0 kcal mol −1 higher in free energy than the global minimum. The Ag + ion in this salt bridge structure is attached to the carboxylate anion of zwitterionic ProGly in which the terminal amino nitrogen is protonated. For all the other complexes studied, the salt bridge structure occurs at much higher energies. All the dipeptide complexes with Ag + , but one, exhibit a di- or tri-coordinate metal where the sites of attachment are amino and carbonyl groups. However, the highest coordination numbers are not always the global minima due to steric costs. The global minimum of the Ag + –GlyProAla complex is the only structure found in this study where the metal is tetra-coordinated, binding to the terminal amino nitrogen and all three carbonyl oxygen atoms. Silver binding to sulphur and imidazole nitrogen atoms of MetGly and GlyHis, respectively, are present in the three most energetically favored species in each of these cases.

We have studied the silver ion affinities of several RCN ligands using density functional theory. It was found that they correlate linearly with experimental proton affinities, a contradiction to the HSAB principle as H + is a ‘hard’ acid, and Ag + is a ‘soft’ acid. This linear correlation between the Ag + and proton affinities diminishes as the number of RCN ligands attached to the Ag + ion increases from one to three. In the third addition step, the silver ion affinities nearly level off in agreement with the expectation that the electron donating or withdrawing properties of the R group become much less important than in the previous two steps, where the positive charge on the metal ion is not well delocalized. Delocalization of the charge of a metal ion occurs only when a sufficiently large number of ligands are attached to the metal ion. When this condition is satisfied, our data suggests that the HSAB principle may be applicable.