Interaction Enthalpy of Side Chain and Backbone Amides in Polyglutamine Solution Monomers and Fibrils

We determined an empirical correlation that relates the amide I vibrational band frequencies of the glutamine (Q) side chain to the strength of hydrogen bonding, van der Waals, and Lewis acid–base interactions of its primary amide carbonyl. We used this correlation to determine the Q side chain carbonyl interaction enthalpy (ΔH_int) in monomeric and amyloid-like fibril conformations of D₂Q₁₀K₂ (Q10). We independently verified these ΔH_int values through molecular dynamics simulations that showed excellent agreement with experiments. We found that side chain–side chain and side chain–peptide backbone interactions in fibrils and monomers are more enthalpically favorable than are Q side chain–water interactions. Q10 fibrils also showed a more favorable ΔH_int for side chain–side chain interactions compared to backbone–backbone interactions. This work experimentally demonstrates that interamide side chain interactions are important in the formation and stabilization of polyQ fibrils.