Linker Effects on Amino Acid and Peptide Recognition by Molecular Tweezers

Abstract

AbstractTransition 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.