A Novel Long‐Range n to π* Interaction Secures the Smallest known α‐Helix in Water

Abstract

The introduction of an amide bond linking side chains of the first and fifth amino acids forms ac yclic pentapeptide that optimally stabilizes the smallest known ahelix in water.T he origin of the stabilization is unclear.T he observed dependence of a-helicity on the solvent and cyclization linker led us to discover an ovel long-range nt op* interaction between amain-chain amide oxygen and auniquely positioned carbonyl group in the linker of cyclic pentapeptides. CD and NMR spectra, NMR and X-ray structures,modelling, and MD simulations reveal that this first example of asynthetically incorporated long-range nt op*C O···C g =O interaction uniquely enforces an almost perfect and remarkably stable peptide a-helix in water but not in DMSO.T his unusual interaction with ac ovalent amide bond outside the helical backbone suggests new approaches to synthetically stabilize peptide structures in water.

Hydrogen Bonds and n → π* Interactions in the Acetylation of Propranolol Catalyzed by Candida antarctica Lipase B: A QTAIM Study

“…We now analyze n → π* interactions, which have been shown to play a role in two scenarios: (i) structure and (ii) reactivity. In the first scenario, this interaction is involved in the stability and preferential conformations of small molecules, peptides, ,− proteins, ,− peptoids, ,, and nucleic acids. , In the second scenario, the n → π* interactions resemble the Bürgi–Dunitz trajectory for nucleophilic addition to the carbonyl group . In the following, the second scenario will be analyzed.…”

Structural and ITC Characterization of Peptide‐Protein Binding: Thermodynamic Consequences of Cyclization Constraints, a Case Study on Vascular Endothelial Growth Factor Ligands

“…In the NMR spectra of peptide 1 c, the linker amide NH resonance was also split into a broad doublet of doublets, whereas for 2 c it was a broad triplet, in agreement with the observation by Hoang et al, who proposed specific n!π* stabilizing interaction in a KxxxD lactam-bridged peptide. [14] The corresponding NH resonances were not observable in 3 c and 4 c because of signal overlap.…”

“…In peptide 1 c, we also observed that the conformation of the lactam was compatible with a n!π* stabilizing interaction involving the linker amide carbonyl π* orbital and the Lys P10 main chain carbonyl n orbital, which was mentioned above (Figure S5). [14] The monocyclic peptides were not co-crystallized, but the v107 peptide:VEGF NMR structure can be used as a model. [8] Despite some sequence differences, all the peptide-protein contacts are equivalent (see Supporting Information for details), except for n Leu 6, which is substituted by a Met in v107.…”

“…Blue: distribution observed in the PDB for unmodified Asp residue (D), [18] or from molecular simulation for D i -K i + 4 (grey) and K i -D i + 4 (orange) lactam-bridged Asp residues in a short α-helix. [14] The lactam bridges and the α-helix fold imposed additional constraints to Asp χ…”

“…Example of an Asp residue involved in lactam bridge.Dashed lines: probability density function of χ 1 . Blue: distribution observed in the PDB for unmodified Asp residue (D),[18] or from molecular simulation for D i -K i + 4 (grey) and K i -D i + 4 (orange) lactam-bridged Asp residues in a short α-helix [14]. The lactam bridges and the α-helix fold imposed additional constraints to Asp χ 1 and shifted the χ 1 distribution of D i -K i + 4 and K i -D i + 4 , prohibiting certain conformations.…”