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.

本研究确立了一项经验相关性，可将谷氨酰胺（glutamine，缩写Q）侧链的酰胺I振动带（amide I vibrational band）频率，与其伯酰胺羰基所参与的氢键（hydrogen bonding）、范德华力（van der Waals）及路易斯酸碱相互作用（Lewis acid–base interactions）的强度相关联。我们借助该相关性，测定了D2Q10K2（缩写为Q10）的单体态与类淀粉样原纤维（amyloid-like fibril）构象中，Q侧链羰基的相互作用焓（ΔHint）。我们通过与实验结果吻合度极佳的分子动力学模拟（molecular dynamics simulations），对上述ΔHint数值进行了独立验证。研究发现，相较于Q侧链与水分子的相互作用，原纤维与单体中的侧链-侧链、侧链-肽主链相互作用在焓层面更具优势。Q10原纤维的侧链-侧链相互作用，相较主链-主链相互作用，同样展现出更优的ΔHint数值。本研究通过实验证实，酰胺侧链间的相互作用对聚谷氨酰胺（polyQ）原纤维的形成与稳定至关重要。