Structural Determinants of Cisplatin and Transplatin Binding to the Met-Rich Motif of Ctr1: A Computational Spectroscopy Approach

Abstract

The cellular uptake of cisplatin and of other platinum-based drugs is mediated by the high-affinity copper transporter Ctr1. The eight-residue long peptide called Mets7 (MTGMKGMS) mimics one of extracellular methionine (Met)-rich motifs of Ctr1. It is an excellent model for investigating the interaction of platinum drugs with Ctr1 under in vitro and in vivo conditions. Some of us have shown that (i) Cisplatin loses all of its ligands upon reaction with Mets7 and the metal ion binds to the three Met residues and completes its coordination shell with a fourth ligand that can be a chloride or a water/hydroxyl oxygen. (ii) Transplatin loses only the chlorido ligands, which are replaced by Met residues. Here, we provide information on the structural determinants of cisplatin/Mets7 and transplatin/Mets7 adducts by computational methods. The predictions are validated against EXAFS, NMR, and CD spectra. While EXAFS gives information restricted to the metal coordination shell, NMR provides information extended to residue atoms around the coordination shell, and finally, CD provides information about the overall conformation of the peptide. This allows us to elucidate the different reaction modes of cisplatin and transplatin toward the peptide, as well as to propose the platinated peptides [PtX](+)-(M*TGM*KGM*S) (X = Cl(-), OH(-)) and trans[Pt(NH3)2](2+)-(M*TGM*KGMS) as the most relevant species occurring in water solution.

Chapter 9. First Principles Methods in Biology: From Continuum Models to Hybrid Ab initio Quantum Mechanics/Molecular Mechanics

“…A recent review reports CPMD/MM applications that address this issue. 169 The method has also recently provided valuable insights on DNA damage 16,[170][171][172][173][174][175] and on the binding of anticancer drugs to DNA [176][177][178][179][180] or to the copper transport protein, [181][182][183] which is supposed to function as a transporter of cisplatin.…”

DichroCalc: Improvements in Computing Protein Circular Dichroism Spectroscopy in the Near-Ultraviolet

“…DichroCalc has been used [17] to compute the CD spectra of amyloid structures, based on MD simulations. Calculated CD spectra have also been used in the comparison of simulated conformations of Mets7, bound and unbound to cis-platin [18]; Mets7 is an eight-residue peptide, which mimics an important function, that is, cellular uptake of platinum-based drugs, of the high-affinity copper influx transporter protein, Ctr1. Simulations of a phosphate binding protein labeled with two rhodamine fluorophores have been conducted [19], because the protein was not amenable to study by X-ray crystallography or NMR spectroscopy; comparison with experimental biophysical data was facilitated by computing the CD from the MD simulations.…”

Permeation of cisplatin through the membranes of normal and cancer cells: a molecular dynamics study

“…Although some studies show a positive correlation between the presence of CTr1 in the membrane and the high transport rate of cisplatin, they do not necessarily show an increase of the cell death rate. This may suggest that cisplatin appears in the cytoplasm in inactivated chemical form after being transported by CTr1 (61,(65)(66)(67). Currently passive diffusion through the lipid bilayer is considered as the only known way of transport of cisplatin in its active form (53,58,65,68).…”