Cyclic Octapeptides Composed of Two Glutathione Units Outperform the Monomer in Lead Detoxification

A rationally-designed scaffold of cyclic octapeptides composed of two units of the natural tripeptide glutathione (GSH) was optimized to strongly and selectively capture toxic lead ions (Pb(II)). Using state-of-the-art computational tools, a list of eleven plausible peptides was shortened to five analogs based on their calculated affinity to Pb(II) ions. We then synthesized and investigated them for their abilities to recover Pb-poisoned human cells. A clear pattern was observed from the in vitro detoxification results, indicating the importance of cavity size and polar moieties to enhance metal capturing. These, together with the apparent benefit of cyclizing the peptides, improved the detoxification of the two lead peptides by approximately two folds compared to GSH and the benchmark chelating agents against Pb poisoning. Moreover, the two peptides did not show any toxicity and, therefore, were thoroughly investigated to determine their potential as next-generation remedies for Pb poisoning

Proton Affinities of Organocatalysts Derived from Pyridine N-oxide

Proton affinities of several efficient organocatalysts METHOX, QUINOX, ANETOX, KOTOX, FUREOX, and FUROOX bearing a pyridine N-oxide or 2,2′-bipyridyl N,N′-dioxide moiety were de-termined by using extended kinetic method and density functional theory calculations. Proton affinities are in the range of 1030–1060 kJ mol–1. Using isodesmic reactions, the effect of combining two pyridine N-oxide units in the neutral and the protonated molecule was studied: The combination of an unfavorable interaction in the former case and a favorable interaction in the latter accounts for the superbasic proper¬ties of 2,2′-bipyridyl N,N′-dioxides. Last but not least, the theoretically predicted pKa in ethanol are 0.1, –2.7, 0.9, 1.8, 1.9, and 2.3 for the METHOX, QUINOX, ANETOX, FUROOX, FUREOX, and KOTOX, respectively

A new insight into the zinc-dependent DNA-cleavage by the colicin E7 nuclease:a crystallographic and computational study

The crystal structure of a colicin E7 metallonuclease mutant complemented by QM/MM calculations suggests an alternative catalytic mechanism of Zn2+-containing HNH nucleases.</p

Catalytic Cycle of Multicopper Oxidases Studied by Combined Quantum- and Molecular-Mechanical Free-Energy Perturbation Methods

We have used combined quantum mechanical and molecular mechanical free-energy perturbation methods in combination with explicit solvent simulations to study the reaction mechanism of the multicopper oxidases, in particular the regeneration of the reduced state from the native intermediate. For 52 putative states of the trinuclear copper cluster, differing in the oxidation states of the copper ions and the protonation states of water- and O2-derived ligands, we have studied redox potentials, acidity constants, isomerisation reactions, as well as water- and O2 binding reactions. Thereby, we can propose a full reaction mechanism of the multicopper oxidases with atomic detail. We also show that the two copper sites in the protein communicate so that redox potentials and acidity constants of one site are affected by up to 0.2 V or 3 pKa units by a change in the oxidation state of the other site

Reorganization Energy for Internal Electron Transfer in Multicopper Oxidases.

We have calculated the reorganization energy for the intramolecular electron transfer between the reduced type 1 copper site and the peroxy intermediate of the trinuclear cluster in the multicopper oxidase CueO. The calculations are performed at the combined quantum mechanics and molecular mechanics (QM/MM) level, based on molecular dynamics simulations with tailored potentials for the two copper sites. We obtain a reorganization energy of 91-133 kJ/mol, depending on the theoretical treatment. The two Cu sites contribute by 12 and 22 kJ/mol to this energy, whereas the solvent contribution is 34 kJ/mol. The rest comes from the protein, involving small contributions from many residues. We have also estimated the energy difference between the two electron-transfer states and show that the reduction of the peroxy intermediate is exergonic by 43-87 kJ/mol, depending on the theoretical method. Both the solvent and the protein contribute to this energy difference, especially charged residues close to the two Cu sites. We compare these estimates with energies obtained from QM/MM optimizations and QM calculations in a vacuum and discuss differences between the results obtained at various levels of theory