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Orthogonal dipolar interactions between amide carbonyl groups.


ABSTRACT: 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...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.

SUBMITTER: Fischer FR 

PROVIDER: S-EPMC2582285 | biostudies-literature | 2008 Nov

REPOSITORIES: biostudies-literature

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Orthogonal dipolar interactions between amide carbonyl groups.

Fischer Felix R FR   Wood Peter A PA   Allen Frank H FH   Diederich François F  

Proceedings of the National Academy of Sciences of the United States of America 20081103 45


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 stabilizin  ...[more]

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