Tunable Control of Polyproline Helix (PPII) Structure via Aromatic Electronic Effects: An Electronic Switch of Polyproline Helix

Abstract

Aromatic rings exhibit defined interactions via the unique aromatic π face. Aromatic amino acids interact favorably with proline residues via both the hydrophobic effect and aromatic–proline interactions, C−H/π interactions between the aromatic π face and proline ring C–H bonds. The canonical aromatic amino acids Trp, Tyr, and Phe strongly disfavor a polyproline helix (PPII) when they are present in proline-rich sequences because of the large populations of cis amide bonds induced by favorable aromatic–proline interactions (aromatic–cis-proline and proline–cis-proline–aromatic interactions). We demonstrate the ability to tune polyproline helix conformation and cis–trans isomerism in proline-rich sequences using aromatic electronic effects. Electron-rich aromatic residues strongly disfavor polyproline helix and exhibit large populations of cis amide bonds, while electron-poor aromatic residues exhibit small populations of cis amide bonds and favor polyproline helix. 4-Aminophenylalanine is a pH-dependent electronic switch of polyproline helix, with cis amide bonds favored as the electron-donating amine, but trans amide bonds and polyproline helix preferred as the electron-withdrawing ammonium. Peptides with block proline–aromatic PPXPPXPPXPP sequences exhibited electronically switchable pH-dependent structures. Electron-poor aromatic amino acids provide special capabilities to integrate aromatic residues into polyproline helices and to serve as the basis of aromatic electronic switches to change structure.

Insights into Thiol–Aromatic Interactions: A Stereoelectronic Basis for S–H/π Interactions

“…7 This approach involves the synthesis of peptides containing the commercially available amino acid 4-iodophenylalanine, followed by site-selective cross-coupling reaction on solid phase on the fully synthesized peptide with thioacetic acid and copper(I)-phenanthroline. In work directed toward the inclusion of thiolphenylalanine in cysteine-rich disulfide-containing peptides, we alternatively developed a solution-phase approach to this amino acid.…”

“…In work directed toward the inclusion of thiolphenylalanine in cysteine-rich disulfide-containing peptides, we alternatively developed a solution-phase approach to this amino acid. 8 The protected Boc-4-iodo-phenylalanine tert -butyl ester readily underwent cross-coupling reaction 7a, 9 , generating the amino acid with a free thiol upon thiolytic reductive workup. The resultant thiol product, Boc-L-4-thiolphenylalanine tert -butyl ester ( 1 , Chart 1), crystallized from ethyl acetate/hexanes.…”

“…2j Similarly, in the structure of 1 , we observed a 99˚ C–S–H bond angle, which is different from that of tyrosine (~120˚) and points to the unique structural possibilities of thiolphenylalanine, in addition to its access to diverse oxidative modifications. 7–8, 26 …”

Perfluoro-tert-butyl Homoserine Is a Helix-Promoting, Highly Fluorinated, NMR-Sensitive Aliphatic Amino Acid: Detection of the Estrogen Receptor·Coactivator Protein–Protein Interaction by 19F NMR

“…(105, 126) Perfluoro- tert -butyl homoserine exhibited one of the higher PPII propensities among studied amino acids (Figure 3, Table 2). The PPII propensity of perfluoro- tert -butyl homoserine was significantly lower than that of proline or leucine, but was similar to that of methionine, lysine, and arginine, as well as homoserine.…”

Supramolecular Chirality in Dynamic Coordination Chemistry

“…Helicity switching between a right-handed B-DNA helix and a left-handed Z-DNA may be involved in regulating gene expression and in DNA processing events [6,7]. Polyproline adopts two helical structures, a right-handed type I helical structure and a left-handed type II helical structure, which are interconverted through a change in media polarity [8] and other external stimuli [9,10]. The cis-trans conversion of peptidyl-prolyl bonds can be catalyzed by prolyl isomerase to change the entire protein structure and to determine the rate of protein folding [11,12].…”