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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Orthogonal Dipolar Interactions Between Amide Carbonyl Groups
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Orthogonal Dipolar Interactions Between Amide Carbonyl Groups

机译：酰胺羰基之间的正交偶极相互作用

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摘要

Orthogonal dipolar interactions between amide C=O bond dipoles are commonly found in crystal structures of small molecules, proteins, and protein-ligand complexes. We herein present the experimental quantification of such interactions by employing a model system based on a molecular torsion balance. Application of a thermodynamic double-mutant cycle allows for the determination of the incremental energetic contributions attributed to the dipolar contact between 2 amide C=O groups. The stabilizing free interaction enthalpies in various apolar and polar solvents amount to -2.73 kJ mol~(-1) and lie in the same range as aromatic-aromatic C-H...π and π-π interactions. High-level intermolecular perturbation theory (IMPT) calculations on an orthogonal acetamide/N-acetylpyrrole complex in the gas phase at optimized contact distance predict a favorable interaction energy of -9.71 kJ mol~(-1). The attractive dipolar contacts reported herein provide a promising tool for small-molecule crystal design and the enhancement of ligand-protein interactions during lead optimization in medicinal chemistry.
机译：酰胺C = O键偶极之间的正交偶极相互作用通常在小分子，蛋白质和蛋白质-配体复合物的晶体结构中发现。本文中我们通过采用基于分子扭转平衡的模型系统，对这种相互作用进行了实验量化。热力学双突变周期的应用允许确定归因于两个酰胺C ＝ O基团之间的偶极接触的增加的能量贡献。在各种非极性和极性溶剂中稳定的自由相互作用焓为-2.73 kJ mol〜（-1），处于与芳族-芳族C-H ...π和π-π相互作用相同的范围内。在最佳接触距离下，气相中正交乙酰胺/ N-乙酰基吡咯配合物的高级分子间扰动理论（IMPT）计算预测了-9.71 kJ mol〜（-1）的有利相互作用能。本文报道的有吸引力的偶极接触为小分子晶体设计和药物化学中铅优化过程中配体-蛋白质相互作用的增强提供了有希望的工具。

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