Ivan Huc

Constructing artificial assemblies that combine proteins and synthetic ligands has been hampered by the lack of protein–ligand interfaces that are sufficiently large and organized to enable precise structural control. Here ribosome display selection is used to identify a protein that binds a helical aromatic foldamer both tightly and selectively through a sizeable surface area. We used this complex as a supramolecular synthon to create well-defined hybrid foldamer–protein architectures. Examples include foldamers that bind two proteins and hold them at a precise distance, proteins that bind two foldamers and crystals in which proteins and foldamers are connected in cyclic or infinite arrays. The modularity of aromatic foldamers brings a further dimension to protein-based assemblies.

DNA mimic foldamers (DMFOs) are helically folded aromatic oligoamides bearing negatively charged side chains that mimic the shape and charge distribution of double-stranded B-DNA. DNA mimicry typically entails the regular alternation of two different aromatic amino acid monomers, M and Q. Here, we introduce a new synthetic approach of (MQ)n oligomers on solid phase that enabled the production of sequences as long as a 100mer, weighing 35 kDa, formally equivalent to a 50-base pair DNA duplex, or equivalent in molecular weight to a 300amino acid protein. The approach takes advantage of dimeric Fmoc-MQ-OH as elementary building blocks. Three such macromonomers were synthesized using Q and M units bearing different side chains. Solid phase synthesis protocols were validated in all three series. Helix handedness was shown to be determined by a single chiral residue. The purified long oligomers were analyzed by reversed phase high-performance liquid chromatography, mass spectrometry, circular dichroism, and nuclear magnetic resonance spectroscopy for their purity, identity, and helix-handedness bias. Clusters of foldamers forming in the presence of Ca2+ could be visualized by cryogenic electron microscopy (cryo-EM), validating their dimensions.

Correction for ‘Structure-based design of an aromatic helical foldamer–protein interface’ by Lingfei Wang et al. , Chem. Sci. , 2025, 16 , 12385–12396, https://doi.org/10.1039/D5SC01826A.

A strategy for developing ferrocene-incorporated heteroditopic macrocycles for the recognition of zwitterionic proline is presented. The receptor features a well-defined helical cavity, and diastereomeric conformers result upon encapsulation of d/l-proline as indicated by X-ray crystallography. Incorporation of a ferrocene unit allows efficient chirality signaling, which is clearly manifested by circular dichroism and NMR spectroscopy upon guest binding. This work demonstrates a viable approach for constructing ditopic hydrogen-bonded aromatic oligoamide macrocycles capable of sensing zwitterionic amino acids.

Preserving the structural integrity of biomimetic foldamers upon surface deposition is essential for their integration into functional molecular architectures and devices. When assembled in well-ordered monolayers, these molecules can exhibit distinctive characteristics. In this study, we investigate the electrospray-controlled ion beam deposition of foldamer molecules in an ultrahigh vacuum (UHV) environment on an Au(111) surface and examine how their conformation depends on the mean landing energy during deposition. At a low mean landing energy of about 0.6 eV, intact foldamers are observed on the surface, whereas higher landing energies predominantly result in unfolded molecules and partially folded states. Additionally, annealing of the substrate converts folded conformations into unfolded ones. These results highlight the importance of soft-landing conditions to maintain hydrogen-bond-stabilized architectures on surfaces, offering a model platform for studying the structure-function relationship of surface-supported thermolabile biomolecules.

Single stranded helically folded aromatic oligoamides bearing anionic phosphonate side chains have been shown to bind to some DNA-binding proteins better than DNA itself. However, these DNA mimic foldamers have...

DNA mimic foldamers are helically folded aromatic oligoamides bearing negatively charged side chains that mimic the shape and charge distribution of double-stranded B-DNA. They have been shown to bind to some DNA-binding proteins better than DNA itself and thus have potential to interfere with DNA-protein interactions. Their structure has been previously characterized in detail by X-ray crystallography. We have now investigated their structural dynamics both computationally and experimentally. The force field parameters of the building blocks required for DNA mimicry were optimized and implemented in AMBER to perform molecular dynamics simulations of the foldamer helices. The position of the negatively charged side chains on the helix, the charge state of the side chains, and the presence of salt were systematically varied. The simulations revealed that the global flexibility parameters for twisting and bending of the foldamer helices are of similar magnitude to those of B-DNA, though distinct kinking events and motions are involved. A range of sequences were then prepared for experimental investigations using ¹H NMR, UV-vis absorption and circular dichroism spectroscopies. Measurements revealed that the foldamer helices are stable over a broad range of temperature, pH and salt conditions in aqueous solutions, but that they nevertheless undergo structural changes when conditions are modified. An assay was developed to quantitatively assess foldamer helix stability through the measurement of the rate of interconversion between right-handed and left-handed diastereomeric conformers. Unexpectedly, suppressing some negatively charged side chains had a destabilizing effect on the helix, suggesting a more complex role of the side chains than electrostatic repulsions.

Kurzzusammenfassung: Es wurde eine Linkereinheit entworfen und synthetisiert, die sowohl als Haarnadelturn in einem DNA‐Duplex als auch als Ankerpunkt für ein aromatisches helikales Foldamer dienen kann, das die Form und Oberflächeneigenschaften von B‐DNA nachahmt. Es wurden Methoden zur Synthese natürlicher und nicht natürlicher chimärer Moleküle entwickelt, die Foldamer und DNA‐Segmente kombinieren. Die Fähigkeit des Linkers, die Helix des Foldamers und die Duplex‐DNA so zu positionieren, dass ihre Ränder und Furchen trotz ihrer völlig unterschiedlichen chemischen Beschaffenheit zueinander passen, wurde mit Hilfe von Einkristall‐Röntgenbeugung, Zirkulardichroismus und Molekülmodellen nachgewiesen. Bio‐Layer‐Interferometrie bestätigte, dass die künstlichen Haarnadel‐DNA‐Duplexe ihre Fähigkeit zur Bindung an DNA‐bindende Proteine behalten. Die chimären Moleküle könnten den Weg zu kompetitiven Inhibitoren von Protein‐DNA‐Wechselwirkungen ebnen, an denen sequenzselektive DNA‐bindende Proteine beteiligt sind.

A linker unit was designed and synthesized that can serve both as a hairpin turn in a DNA duplex and anchor point for an aromatic helical foldamer mimicking the shape and surface properties of B‐DNA. Methods were developed to synthesize natural/non‐natural chimeric molecules combining foldamer and DNA segments. The ability of the linker to position the foldamer helix and the duplex DNA so that their rims and grooves are in register, despite their completely different chemical nature, was demonstrated using single crystal X‐ray diffraction, circular dichroism and molecular models. Bio‐layer interferometry confirmed that artificial hairpin DNA duplexes keep their ability to bind to DNA binding proteins. The chimeric molecules may pave the way to competitive inhibitors of protein‐DNA interactions involving sequence‐selective DNA‐binding proteins.