Prediction of structural properties of cisplatin/protein adducts from QM/MM methods

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The anticancer drug cisplatin targets the nuclear DNA of tumor cells. Albeit very efficient, cisplatin efficiency is severely hampered by the emergence of drug-resistance. Several groups in the world have begun an intensive experimental investigation on the cellular biology of the drug, in an attempt to address this issue [Wa05]. In particular, it has been discovered that the drug influx is governed by copper transport proteins, including the so-called Ctr1 protein, and that drug efflux/sequestration involves the copper chaperone Atox1 and the copper pumps ATP7B. Experimental biophysical methods have provided some insights into the structural determinants of the adducts of these proteins with cisplatin, albeit detailed structural information is still lacking. Here we will use a variety of computational tools, spanning from QM/MM simulations based on density functional theory, classical molecular dynamics to force-matching procedure to investigate some platinated proteins involved in cisplatin transport for which experimental biophysical data are available. These are: (i) Peptide mimics of Ctr1, which have been characterized experimentally in vitro by NMR spectroscopy, circular dichroism, and X-ray absorption spectroscopy; (ii) Platinated Atox1 and ATP7B proteins, for which both in vitro and in cell cisplatin binding experiments are available. Most of these experiments are carried out by experimental collaborators in this project in Germany and in Italy. Comparison between calculated and experimental parameters might establish a rather general protocol to investigate relevant aspects of the cellular biology of anticancer Pt drugs.