Solution Observation of Dimerization and Helix Handedness Induction in a Human Carbonic Anhydrase–Helical Aromatic Amide Foldamer Complex

Abstract

The design of synthetic foldamers to selectively bind proteins is currently hindered by the limited availability of molecular data to establish key features of recognition. Previous work has described dimerization of human carbonic anhydrase II (HCA) through self-association of a quinoline oligoamide helical foldamer attached to a tightly binding HCA ligand. A crystal structure of the complex provided atomic details to explain the observed induction of single foldamer helix handedness and revealed an unexpected foldamer-mediated dimerization. Here, we investigated the detailed behavior of the HCA-foldamer complex in solution by using NMR spectroscopy. We found that the ability to dimerize is buffer-dependent and uses partially distinct intermolecular contacts. The use of a foldamer variant incapable of self-association confirmed the ability to induce helix handedness separately from dimer formation and provided insight into the dynamics of enantiomeric selection.

Computational Prediction and Rationalization, and Experimental Validation of Handedness Induction in Helical Aromatic Oligoamide Foldamers

“…Their design followed the same simple principle as the design of 2 a / 2 b , that is, that a stereogenic center has a higher chance to promote helix handedness bias if it is placed close to the aromatic backbone. In the case of compounds 3 a to 6 b , the stereogenic center is located at the C terminus of the helix, thus leaving the N terminus available for further functionalization at the end of solid phase oligomer synthesis . To consider both the acid and the methyl ester forms of proline, we carried out metadynamics simulations for four pairs of enantiomers: 3 a/3 b and 4 a/4 b are the SS / RR and RS / SR enantiomers in the methyl ester form, respectively; 5 a/5 b and 6 a/6 b are their acid form counterparts.…”

“…Oligoquinoline carboxamide helical foldamers can be equipped with a variety of proteinogenic side chains that diverge from the helices. Depending on the resulting sequence, selective interactions may occur with nucleic acids or with proteins . Interactions were shown to be diastereoselective.…”

Protein Surface Mimetics: Understanding How Ruthenium Tris(Bipyridines) Interact with Proteins

“…One such strategy is the surface mimetic approach: protein surface mimetics are a class of molecular structures that utilize a scaffold to project multiple binding groups over a large area of protein surface to achieve high‐affinity protein binding. Several different scaffolds have been used as protein surface mimetics, including calixarenes, porphyrins, dendrimers, metal complexes, nanoparticles, and others …”

A Binary Bivalent Supramolecular Assembly Platform Based on Cucurbit[8]uril and Dimeric Adapter Protein 14‐3‐3

“…[5][6][7][8][9][10] These prior studies have laid the foundation for supramolecularly controlled protein dimerization, functioning, and assembly orthogonal to natural recognition and switching events. [3,[11][12][13] Notable examples include the dimerization of carbonic anhydrase by the use of as ynthetic foldamer platform [14,15] and the cucurbit[8]uril (Q8)-mediated functional reconstitution of as plit luciferase enzyme.[16] Thes tudy and modulation of protein-protein interactions (PPIs) is one of the most progressive areas of chemical biology and important for both fundamental research and drug discovery. [17,18] Protein assemblies frequently employ multivalent binding events,but the switching of this multivalency, for example between mono-and bivalent states,i sn ot readily modulated by classical small molecules.…”