Quantifying Amide-Aromatic Interactions at Molecular and Atomic Levels: Experimentally Determined Enthalpic and Entropic Contributions to Interactions of Amide spO, N, C and spC Unified Atoms with Naphthalene spC Atoms in Water.

In addition to amide hydrogen bonds and the hydrophobic effect, interactions involving π-bonded sp 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 spO with amide spN unified atoms (presumably C═O···H-N hydrogen bonds) and amide/aromatic spC (lone pair π, n-π*) are particularly favorable. SpC-spC (hydrophobic), spC-spC (hydrophobic, CH-π), spC-spC (hydrophobic, π-π), and spC-spN interactions are favorable, spC-spN interactions are neutral, while spO-spO and spN-spN self-interactions and spO-spC interactions are unfavorable. Here, from determinations of favorable effects of 14 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 spO, spN, spC, and spC unified atoms with aromatic spC 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 spO-aromatic spC interaction is enthalpy-driven and entropically unfavorable, consistent with direct chemical interaction (e.g., lone pair-π), while amide spC- and spC-aromatic spC interactions are entropy-driven and enthalpically unfavorable, consistent with hydrophobic effects. These findings are relevant for interactions involving π-bonded sp atoms in protein processes.