Electronic and Steric Control of n→π* Interactions: Stabilization of the α‐Helix Conformation without a Hydrogen Bond

Abstract

The preferred conformations of peptides and proteins are dependent on local interactions that bias the conformational ensemble. The n→π* interaction between consecutive carbonyls promotes compact conformations, including the α‐helix and polyproline II helix. In order to further understand the n→π* interaction and to develop methods to promote defined conformational preferences through acyl N‐capping motifs, a series of peptides was synthesized in which the electronic and steric properties of the acyl group were modified. Using NMR spectroscopy, van't Hoff analysis of enthalpies, X‐ray crystallography, and computational investigations, we observed that more electron‐rich donor carbonyls (pivaloyl, iso‐butyryl, propionyl) promote stronger n→π* interactions and more compact conformations than acetyl or less electron‐rich donor carbonyls (methoxyacetyl, fluoroacetyl, formyl). X‐ray crystallography indicates a strong, electronically tunable preference for the α‐helix conformation, as observed directly on the φ and ψ torsion angles. Electron‐donating acyl groups promote the α‐helical conformation, even in the absence of the hydrogen bonding that stabilizes the α‐helix. In contrast, electron‐withdrawing acyl groups led to more extended conformations. More sterically demanding groups can promote trans amide bonds independent of the electronic effect on n→π* interactions. Chloroacetyl groups additionally promote n→π* interactions through the interaction of the chlorine lone pair with the proximal carbonyl π*. These data provide additional support for an important role of n→π* interactions in the conformational ensemble of disordered or unfolded proteins. Moreover, this work suggests that readily incorporated acyl N‐capping motifs that modulate n→π* interactions may be employed rationally to promote conformational biases in peptides, with potential applications in molecular design and medicinal chemistry.

The Distinct Conformational Landscapes of 4S‐Substituted Prolines That Promote an endo Ring Pucker

“…The nitrobenzoate group promotes crystal formation in compounds. Within 4 R ‐substituted hydroxyproline nitrobenzoates, we previously observed that the electronic properties of the acyl capping group dramatically impacted the ϕ and ψ torsion angles and n→π* interaction intercarbonyl distances, consistent with stronger n→π* interactions with more electron‐rich acyl donor carbonyls . Therefore, crystallization was attempted on all compounds, in order to identify the inherent conformational effects of 4 S ‐substituted nitrobenzoates and to examine the ability of acyl donor groups to modulate the conformational preferences.…”

“…[4] We previously demonstrated that the interaction strength of an n!p*i nteraction could be modulated by the identity of acyl capping groups that change the electronic properties of the donorc arbonyl. [5] These experiments were conducted using the 4R-nitrobenzoate ester of hydroxyproline, which strongly promotes an exo ring pucker and thus promotes conformationsw ith af avorable n!p*i nteraction. [6] The observed conformations of 4-substituted prolines are dependent on the stereochemistry and the balance of the electronic versus steric effects of the 4-substituent.…”

Steric as well as n→π* Interaction Controls the Conformational Preferences of Phenyl Acetate: Gas‐phase Spectroscopy and Quantum Chemical Calculations

“…Recently, Zondlo and co‐workers as well as Reddy et al. have demonstrated through NMR spectroscopy and quantum chemistry calculations of acyl N ‐cap proline derivatives that preferences toward a defined conformation can be modulated through steric and electronic control of the n→π* interactions by varying the bulkiness of the acyl substitution present there . Blackwell and co‐workers have also reported that n→π* interaction and steric repulsion can regulate the cis / trans isomerization ratios of peptoid oligomers .…”

“…In principle, the effect of substitution, specially at the n→π* donor (i.e., C=O group), is three‐fold. Substitution of the electron‐donating group (EDG) on the n→π* donor increases the strength of the n→π* interaction by increasing the electron density over the carbonyl oxygen atom while the electron‐withdrawing group (EWG) on the n→π* donor decreases the strength of this interaction by pulling the electron density away from the carbonyl oxygen atom . The substituent on the n→π* donor can also introduce steric repulsion in one of the conformers by rendering conformational preference of the other.…”

“…The substituent on the n→π* donor can also introduce steric repulsion in one of the conformers by rendering conformational preference of the other. There can be additional electronic effects by the substituent on the C=O moiety through hyperconjugation . There are many reports in the literature showing the electronic and steric control of conformational populations of molecular systems .…”