## 5 Conclusions  
Molecular dynamics simulations and free energy calculations for the constructed apo-Atox1, CisPt + Atox1, TransPt + Atox1, OxaliPt + Atox1, CisPt + 2 Atox1, TransPt + 2 Atox1 and OxaliPt + 2 Atox1 models have been performed to address the interaction properties of the platinum agents and the Atox1 protein. All the cisplatin, transplantin and oxaliplatin agents could respectively combine with a monomeric Atox1 protein and a dimeric Atox1 protein to form a stable complex due to the covalent interaction of the platinum center of each platinum agent with the binding sites in the Atox1 protein. The calculated binding free energies for the OxaliPt + Atox1 model, except for the covalent interactions between the platinum center and the protein, suggested that the affinity of the oxaliplatin ligand with the Atox1 protein provide the extra interaction. However, such extra interaction in the CisPt + Atox1 and TransPt + Atox1 models is insignificant. The corresponding visual structure analysis proposed that the oxaliplatin agent binding to the Atox1 protein may lead to a larger unfolding and deformation of the Atox1 protein over those in the CisPt + Atox1 and TransPt + Atox1 models. The hydrogen bonds and hydrophobic interactions at the N-H/C-H groups of the oxaliplatin ligand and the residues Cys15 of the \(\beta\)1-\(\alpha\)1 loop, Ala18 of the \(\alpha\)1 helix and Thr58 of the \(\alpha\)2-\(\beta\)4 loop in the Atox1 protein, and the binding pocket with the size of 82.6 A\({}^{2}\)/61.5 A\({}^{3}\) around the binding sites were detected, which support the calculated affinity of the oxaliplatin agent to the Atox1 protein. For the three platinum agents binding to the Atox1 dimer, the binding free energy calculations suggest that no extra interactions come from the platinum ligand-Atox1 dimer interface except for the covalent interaction between the platinum center and the protein. However, the extra interactions between the residues Arg21, Ala18, Gly59, Thr58 of \(\alpha\)1 helix/\(\alpha\)2-\(\beta\)4 loop of the Atox1 A protein and the residues Cys15, Arg21, Gly59, Thr61, Ala18 of those of the Atox1 B protein for the CisPt + 2 Atox1 and OxaliPt + Atox1 models at the Atox1 protein-Atox1 protein interface were found due to the cis conformations of the cisplatin and oxaliplatin agents. However, such extra interaction in the TransPt + Atox1 models might be insignificant due to its trans conformation. The average structure analysis speculated that the two Atox1 proteins exhibit the structural feature of the asymmetric dimers for all the three ternary models, which supports the experimental suggestion. The asymmetric structural characteristics were mainly reflected in the rearrangement of residues and the differences of the centroid distances in the two Atox1 proteins. These results might provide useful insights into understanding the interaction mechanism of platinum agents and the Atox1 protein and the experimental observations of uptake/efflux of the platinum agents in the cytoplasm.  
The authors acknowledge research support from the National Science Foundation of China (No. 20973024, 21073015, 21131003 and 21271029); and the Major State Basic Research Development Programs (grant No. 2011 CB808500).  
The authors declare no conflict of interest.