Abstract
We carried out molecular dynamics simulations and free energy calculations for a series of binary and ternary models of the cisplatin, transplatin and oxaliplatin agents binding to a monomeric Atox1 protein and a dimeric Atox1 protein to investigate their interaction mechanisms. All three platinum agents could respectively combine with the monomeric Atox1 protein and the dimeric Atox1 protein to form a stable binary and ternary complex due to the covalent interaction of the platinum center with the Atox1 protein. The results suggested that the extra interaction from the oxaliplatin ligand–Atox1 protein interface increases its affinity only for the OxaliPt + Atox1 model. The binding of the oxaliplatin agent to the Atox1 protein might cause larger deformation of the protein than those of the cisplatin and transplatin agents due to the larger size of the oxaliplatin ligand. However, the extra interactions to facilitate the stabilities of the ternary CisPt + 2Atox1 and OxaliPt + 2Atox1 models come from the α1 helices and α2-β4 loops of the Atox1 protein–Atox1 protein interface due to the cis conformation of the platinum agents. The combinations of two Atox1 proteins in an asymmetric way in the three ternary models were analyzed. These investigations might provide detailed information for understanding the interaction mechanism of the platinum agents binding to the Atox1 protein in the cytoplasm.
Highlights
The classical anticancer platinum agents, such as cisplatin [cis-diamminedichloroplatinum (II)], transplatin [trans-diamminedichloroplatinum (II)] and oxaliplatin [1,2-diaminocyclohexaneoxalateplatinum (II)], were used widely in clinical therapy effectively against several common types of tumors [1,2,3,4,5,6], such as ovarian, testicular and lung cancer tumors
The ligand of oxaliplatin agent is located at the α1 N-terminal and the α2 C-terminal, which causes the movement of α1 helix close to the β-sheet and away from the α2 helix, itself bend of α1 helix, and the increase of intersheet angle of β1 and β3 strands by ~9° compared with that in the apo-Atox1 model
The binding of the cisplatin and the transplatin agents to the Atox1 protein in the CisPt + Atox1 and TransPt + Atox1 models does not cause any change of the intersheet angle between the β1 and β3 strands over that in the apo-Atox1 model due to the small sizes of the ligands in the two agents
Summary
The classical anticancer platinum agents, such as cisplatin [cis-diamminedichloroplatinum (II)], transplatin [trans-diamminedichloroplatinum (II)] and oxaliplatin [1,2-diaminocyclohexaneoxalateplatinum (II)], were used widely in clinical therapy effectively against several common types of tumors [1,2,3,4,5,6], such as ovarian, testicular and lung cancer tumors. The mechanism of the platinum agents against tumor is thought to be that the Pt (II) center attacks DNA through the contacts of covalent bonds with the N7 atoms of guanines of the DNA molecule in order to prevent the replication and transcription of DNA, to lead to the cell apoptosis [7,8,9,10]. The platinum agents transiting the nuclear membranes and reacting with DNA play a key role in improving the therapeutic efficacy. The efficacy of these platinum agents is restricted by the reduced uptake to the cytoplasm and increased efflux, decreasing the possibility of the DNA target. The platinum agents can react rapidly with some macromolecules in the cytoplasm, especially thiol compounds, and become invalid before entering cell nucleus [11,12]. The studies on the resistance mechanism of the platinum agents and the interactions between the platinum agents and the biomacromolecules have become a hot topic in recent years
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