Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 105, Issue 45, Pages 17290-17294Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0806129105
Keywords
mutant cycle; protein folding; torsion balance; medicinal chemistry
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Funding
- ETH Research Council
- Fonds der Chemischen Industrie
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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 center dot center dot center dot pi and pi-pi 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.
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