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Fast lateral proton migration along membranes is of vital importance for cellular energy homeostasis and various proton-coupled transport processes. It can only occur if attractive forces keep the proton at the interface. How to reconcile this high affinity to the membrane surface with high proton mobility is unclear. Here, we tested whether a minimalistic(More)
The clinical efficacy of the widely used anticancer drug cisplatin is severely limited by the emergence of resistance. This is related to the drug binding to proteins such as the copper influx transporter Ctr1, the copper chaperone Atox1, and the copper pumps ATP7A and ATP7B. While the binding modes of cisplatin to the first two proteins are known, the(More)
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(More)
We demonstrate the feasibility of estimating protein-ligand binding free energies using multiple rigid receptor configurations. On the basis of T4 lysozyme snapshots extracted from six alchemical binding free energy calculations with a flexible receptor, binding free energies were estimated for a total of 141 ligands. For 24 ligands, the calculations(More)
We investigate the relationship between the number of intermediate thermodynamic states along a pathway and the precision of free energy estimates. With a sufficient number of states, the asymptotic variance collapses as a function of the total sample size. Our analytical result is corroborated by replica exchange molecular dynamics simulations of model(More)
Cisplatin is one of the most used anticancer drugs. Its cellular influx and delivery to target DNA may involve the copper chaperone Atox1 protein. Although the mode of binding is established by NMR spectroscopy measurements in solution-the Pt atom binds to Cys12 and Cys15 while retaining the two ammine groups-the structural determinants of the adduct are(More)
Cisplatin cures testicular and ovarian cancers with unprecedented potency. It induces its beneficial activity by covalently binding to DNA. Repair enzymes, which remove the platinated lesions from DNA, cause drug resistance. Chromosomal High Mobility Group Box proteins (HMGB) may interfere with this process by binding to platinated DNA. Using 8 μs(More)
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