Quantifying Amide-Aromatic Interactions at Molecular and Atomic Levels: Experimentally-determined Enthalpic and Entropic Contributions to Interactions of Amide sp(2)O, N, C and sp(3)C Unified Atoms with Naphthalene sp(2)C Atoms in Water

In addition to amide hydrogen bonds and the hydrophobic effect, interactions involving π-bonded sp(2) atoms of amides, aromatics and other groups occur in protein self-assembly processes including folding, oligomerization and condensate formation. These interactions also occur in aqueous solutions of amide and aromatic compounds, where they can be quantified. Previous analysis of thermodynamic coefficients quantifying net-favorable interactions of amide compounds with other amides and aromatics revealed that interactions of amide sp(2)O with amide sp(2)N unified atoms (presumably C=O···H-N hydrogen bonds) and amide/aromatic sp(2)C (lone pair-π, n-π*) are particularly favorable. Sp(3)C-sp(3)C (hydrophobic), sp(3)C-sp(2)C (hydrophobic, CH-π), sp(2)C-sp(2)C (hydrophobic, π-π) and sp(3)C-sp(2)N interactions are favorable, sp(2)C-sp(2)N interactions are neutral, while sp(2)O-sp(2)O and sp(2)N-sp(2)N self-interactions and sp(2)O-sp(3)C interactions are unfavorable. Here, from determinations of favorable effects of fourteen amides on naphthalene solubility at 10, 25 and 45 °C, we dissect amide-aromatic interaction free energies into enthalpic and entropic contributions and find these vary systematically with amide composition. Analysis of these results yields enthalpic and entropic contributions to intrinsic strengths of interactions of amide sp(2)O, sp(2)N, sp(2)C and sp(3)C unified atoms with aromatic sp(2)C atoms. For each interaction, enthalpic and entropic contributions have the same sign and are much larger in magnitude than the interaction free energy itself. The amide sp(2)O-aromatic sp(2)C interaction is enthalpy-driven and entropically unfavorable, consistent with direct chemical interaction (e.g. lone pair-π) while amide sp(3)C- and sp(2)C-aromatic sp(2)C interactions are entropy-driven and enthalpically unfavorable, consistent with hydrophobic effects. These findings are relevant for interactions involving π-bonded sp(2) atoms in protein processes.