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 (ΔHint) in monomeric and amyloid-like fibril conformations
of D2Q10K2 (Q10). We independently
verified these ΔHint 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 ΔHint 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.