Molecular tweezers with varying anions: a comparative study.

Selective binding of the phosphate-substituted molecular tweezer 1a to protein lysine residues was suggested to explain the inhibition of certain enzymes and the aberrant aggregation of amyloid petide Aß42 or α-synuclein, which are assumed to be responsible for Alzheimer's and Parkinson's disease, respectively. In this work we systematically investigated the binding of four water-soluble tweezers 1a-d (substituted by phosphate, methanephosphonate, sulfate, or O-methylenecarboxylate groups) to amino acids and peptides containing lysine or arginine residues by using fluorescence spectroscopy, NMR spectroscopy, and isothermal titration calorimetry (ITC). The comparison of the experimental results with theoretical data obtained by a combination of QM/MM and ab initio(1)H NMR shift calculations provides clear evidence that the tweezers 1a-c bind the amino acid or peptide guest molecules by threading the lysine or arginine side chain through the tweezers' cavity, whereas in the case of 1d the guest molecule is preferentially positioned outside the tweezer's cavity. Attractive ionic, CH-π, and hydrophobic interactions are here the major binding forces. The combination of experiment and theory provides deep insight into the host-guest binding modes, a prerequisite to understanding the exciting influence of these tweezers on the aggregation of proteins and the activity of enzymes.

Molecular tweezers modulate 14-3-3 protein-protein interactions.

Supramolecular chemistry has recently emerged as a promising way to modulate protein functions, but devising molecules that will interact with a protein in the desired manner is difficult as many competing interactions exist in a biological environment (with solvents, salts or different sites for the target biomolecule). We now show that lysine-specific molecular tweezers bind to a 14-3-3 adapter protein and modulate its interaction with partner proteins. The tweezers inhibit binding between the 14-3-3 protein and two partner proteins--a phosphorylated (C-Raf) protein and an unphosphorylated one (ExoS)--in a concentration-dependent manner. Protein crystallography shows that this effect arises from the binding of the tweezers to a single surface-exposed lysine (Lys214) of the 14-3-3 protein in the proximity of its central channel, which normally binds the partner proteins. A combination of structural analysis and computer simulations provides rules for the tweezers' binding preferences, thus allowing us to predict their influence on this type of protein-protein interactions.

An unexpected and easy way of freezing the configuration of a triaryl phosphane oxide.

Configurationally stable triaryl phosphane oxides are important for reactions with transfer of chiral information. Apart from introducing bulky substituents to suppress fast inversion of helicity at room temperature, the use of a second chiral element which induces chirality in the triaryl phosphane oxide, so that it adopts only one configuration, is suitable. With regard to chirality transfer, C(2)-symmetric imidazole cyclopeptides were tested for obtaining a configurationally stable phosphane oxide. Density functional calculations showed almost equal energies of the three possible triaryl phosphane oxides (MMM)-1, (PPP)-1, and (MP)-1. Surprisingly, after synthesis only the MMM conformer is present in solution, and its configurational stability was proved by variable-temperature and 2D NMR experiments as well as CD measurements. In view of the results of the DFT calculations, formation of stable (MMM)-1 cannot be explained thermodynamically but by kinetic reaction control. This concept of freezing the conformation of a triaryl phosphane oxide can in future be used to easily prepare configurationally stable stereoisomeric propellerlike compounds.

Artificial synthetic receptors as regulators of protein activity.

This article discusses most recent work and progress in the direction of a rational design of small molecule receptors that efficiently interfere with the biological function of a particular receptor or enzyme-some of which are therapeutically relevant. More specifically, the following topics are highlighted here: the inhibition of voltage-dependent potassium channels of the K(v)1.x family by designed porphyrin and calix[4]arene ligands, the structural and functional recovery of the tetramerization domain of mutated P53 protein by tailored calix[4]arene ligands and the control over LDH activity by supramolecular signaling. Finally a new way to modulate NAD(+)-dependent enzymatic activities by molecular clips and tweezers is presented.