Linker Effects on Amino Acid and Peptide Recognition by Molecular Tweezers

Abstract

Transition from monotopic symmetrical to ditopic unsymmetrical molecular recognition frequently occurs when a general, powerful, but unspecific receptor molecule is transformed into a specific ditopic host. Especially in water, this endeavor is accompanied by great challenges, comprising, among other things, host–guest orientation, orthogonal recognition modes, and the nature of the linker unit. This work presents a case study on a powerful general host for basic amino acids and peptides. The symmetrical molecular tweezer skeleton was systematically desymmetrized and modified with various common linker units, and the profound influence of these changes on the molecular recognition profile was studied in detail by NMR spectroscopy, fluorescence titrations, X‐ray crystallography, and molecular simulations. A number of diverse effects were revealed that could be attributed to the chemical nature of the different linkers. In general, long alkyl tethers block the cavity of the tweezers by van der Waals contacts to CH groups around its entrance; alkoxyalkyl tethers likewise lower tweezer affinities for basic amino acids by competing self‐inclusion. As a general trend, affinities for linkers with ester and carboxylate moieties were substantially higher than those for tethers with ethers and alcohols, likely because the electron‐rich carbonyl group keeps the cavity open. Additional hydrogen bonds between the linker unit and suitable amino acid or peptide guests greatly support the complexation process; finally, high solvent polarity and salt load shift the binding equilibrium from external ion pairing to guest inclusion.

Molecular tweezers for lysine and arginine – powerful inhibitors of pathologic protein aggregation

“…1g in turn is the starting material for the unsymmetrically substituted tweezers 1h–n which are also water-soluble. 34 …”

“…The 1 H NMR spectra of the less polar tweezers 1d,f and 1h–n are not significantly concentration-dependent, so that all these benzene tweezers exist as monomers in dilute aqueous solution. In the 1 H NMR spectra of 1k and 1l the signals assigned to the methyl group of the sidechain (R 2 = OCH 2 CH(OH)CH 2 OCH 2 CH 3 or OCH 2 CH 2 CO 2 CH 2 CH 3 ) display an upfield shift of Δ δ ≈ 0.5 or 2.0 ppm 34 indicating that the methyl groups points inside the cavity comparable to the original tweezer 1 (R 1 = R 2 = OCH 2 CH 2 CO 2 CH 2 CH 3 ). 7, 26, 27 Such self-inclusion phenomena may also hinder guest binding.…”

“…8, 32, 33 The monophosphate-substituted tweezers 1h–n turned out to be water-soluble, too, so that in principle, a second binding site at the central benzene bridge can be used to attach an additional recognition site for ditopic peptide and protein recognition. 34, 35 A systematic study of the influence of different anions and linkers on mono- and disubstituted tweezers has spurred an investigation of their potential application as new tools for peptide and protein recognition. In the past decade, we unraveled the potential of molecular tweezers with their unique binding mode to counteract and revert pathologic aggregation of amyloidogenic peptides and proteins, rendering them promising candidates for disease-modifying therapy of major neurological disorders.…”

Supramolecular Chemistry Targeting Proteins

“…This MT can bind biologically relevant cationic peptides with binding affinities in the micromolar range. 37 − 39 The cationic amino acid residues thread through the cavity of the MT, which stabilizes the host–guest complex via CH−π, van der Waals, electrostatic, and hydrogen-bonding interactions ( Figure 2 b). 38 , 39 The effect of different functionalities has been extensively studied by NMR, ITC, fluorescence titration, crystallography, and molecular simulation studies.…”

“…Long alkyl tethers were found to induce host–host self-inclusion, while linkers including esters or caboxylates outperformed ethers and alcohols by keeping the cavity open. 37 The strong contribution of hydrophobic interactions was demonstrated through the monitoring of shifts in characteristic 1 H NMR peaks in methanol. In this case, host–guest complexation was dominated by electrostatic interactions with anionic linkers rather than the hydrophobic effect, leading to peripheral complexation with the tweezer.…”