Structure of a Complex Formed by a Protein and a Helical Aromatic Oligoamide Foldamer at 2.1 Å Resolution

Abstract

In the search of molecules that could recognize sizeable areas of protein surfaces, a series of ten helical aromatic oligoamide foldamers was synthesized on solid phase. The foldamers comprise three to five monomers carrying various proteinogenic side chains, and exist as racemic mixtures of interconverting right-handed and left-handed helices. Functionalization of the foldamers by a nanomolar ligand of human carbonic anhydrase II (HCA) ensured that they would be held in close proximity to the protein surface. Foldamer-protein interactions were screened by circular dichroism (CD). One foldamer displayed intense CD bands indicating that a preferred helix handedness is induced upon interacting with the protein surface. The crystal structure of the complex between this foldamer and HCA could be resolved at 2.1 Å resolution and revealed a number of unanticipated protein-foldamer, foldamer-foldamer, and protein-protein interactions.

Handedness preference and switching of peptide helices. Part I: Helices based on protein amino acids

“…Moreover, other very recent, intriguing results will greatly stimulate additional research in the fundamental field (chiral helix···helix interactions) of biomolecular processes. They include (i) stereoselectivity of the self‐assembly of left‐handed and right‐handed peptide screws with generation of novel collagen triple helix mimetics, using (Pro‐Pro‐Gly) 10 enantiomeric sequences as minimal building blocks ; (ii) polymorphism complexity (twist, chirality, and handedness inversion) exhibited by self‐aggregated peptides resulting in amyloid fibrils ; and (iii) preferred handedness of helical foldamers induced upon interaction with a protein surface .…”

Protein Camouflage: Supramolecular Anion Recognition by Ubiquitin

“…[1][2][3][4] The topic is particularly attractive in view of 1) the wide variety of ligands provided by supramolecular chemistry,a nd 2) the continuing challengeo ftargeting protein surfaces, with their unique patchworks of hydrophobic, polar and charged regions. Efforts to approximate protein surfaces with supramolecular ligands have involved calixarenes, [1,[5][6][7][8][9][10][11][12] crown ethers, [13][14][15] curcurbiturils, [16][17][18][19] foldamers, [20][21][22][23] porphyrins [24][25][26][27][28][29][30][31] andt weezers. [2,[31][32][33] Recent attention has focusedo n the cationic side chains of lysine and arginine as potentialt argets that protrudei nvitinglyf rom the protein surface.…”

Controlling Helix Handedness in Water‐Soluble Quinoline Oligoamide Foldamers

“…When equilibrium deviates from a 50:50 mixture, CD bands emerge. This technique has recently been used to screen short quinoline oligoamide sequences tethered to human carbonic anhydrase II (HCA) through a ligand (Figure 2), and a sequence was identified that not only possessed affinity for the protein surface but also induced the formation of a new HCA dimer 5. The induction of helix handedness has also been observed between a fully cationic side‐chain‐functionalized tetramer and G‐quadruplex DNA6 and between helical capsules and their chiral guests 7.…”