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-H⅐ ⅐ ⅐ and -interactions. High-level intermolecular perturbation theory (IMPT) calculations on an orthogonal acetamide/Nacetylpyrrole 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.mutant cycle ͉ protein folding ͉ torsion balance ͉ medicinal chemistry D ipolar contacts involving organic bond dipoles and a carbonyl group, or a pair of carbonyl groups are commonly found both in chemistry and biology (1). On the basis of an analysis of crystal structures of small molecules, proteins, and protein-ligand complexes, it is theorized that, owing to steric constraints, these dipoles preferentially adopt an orthogonal alignment at closest contact distance (Fig. 1). For their expected weakness, the contributions of these interactions have previously been neglected in the study of inter-and intramolecular contacts. Recently, we have been able to determine the free interaction enthalpy between a C-F and a CϭO bond dipole ranging between Ϫ0.8 kJ mol Ϫ1 and Ϫ1.2 kJ mol Ϫ1 (2, 3). Despite the evident importance of orthogonal interactions between carbonyl dipoles for crystal packing (4-9), peptide secondary structure (10-12), and medicinal chemistry (13), no experimental quantification of the energetic contributions of such interactions has been reported so far. Intermolecular perturbation theory (IMPT) calculations performed by Allen et al. (9) assessed the interaction energy for a perpendicular propan-2-one dimer at an optimal contact distance of d O⅐ ⅐ ⅐CϭO ϭ 3.02 Å to amount to Ϫ7.6 kJ mol Ϫ1 , comparable to the strength of weak hydrogen bonds. To provide experimental proof for the favorable energetic contributions attributed to orthogonal dipolar carbonylcarbonyl interactions, we embarked on their determination. We chose to investigate a monomolecular model system, based on the Wilcox molecular torsion balance (14-16), providing for the determination of weak interactions with a greater accuracy and geometric control than given by the study of bimolecular chemical or biological complexes. The primary noncovalent interaction, an aromatic-aromatic edge-to-face C-H⅐ ⅐ ⅐ contact, prearranges the functional groups bearing the i...

Preferred Configurations of Peptide–Peptide Interactions

“…Their mutual orientation can be either parallel or perpendicular 1,2,17 . Any such attraction has been attributed by some to simple dipole-dipole forces 1,3,5,12 whereby the negatively charged O approaches the C of the other carbonyl which is of opposite charge. Another scenario considers n→π* charge transfer from the O lone pairs to the carbonyl antibonding orbital of the other subunit 4,6,10,11,17 .…”

“…Calculations 4 of pairs of esters pointed toward charge transfer from the lone pair of one O to the π* antibond of the other. A perpendicular arrangement of carbonyl groups was tested via model systems 5 where it was found to be stabilizing albeit only weakly, comparable to a CH··π H-bond. However, the calculations assumed a particular orientation, and did not test to determine whether or not this was a true minimum in the surface.…”

Cis–Trans Amide Bond Rotamers in β-Peptoids and Peptoids: Evaluation of Stereoelectronic Effects in Backbone and Side Chains

“…11,16−18 Electronic n → π* interactions 19 have also been proposed to take part in the stabilization of secondary structures of peptoids. 8,9 These interactions involve donation of a lone pair from a carbonyl oxygen atom into an empty π* orbital of carbon atom of another carbonyl or an aromatic ring ( Figure 1C) 20 and are optimal when mimicking the Burgi− Dunitz trajectory for nucleophilic attack. 21 The β-peptides ( Figure 1A), on the other hand, retain the capability to form intramolecular hydrogen-bond networks to stabilize secondary structures, while the geometry of known helices is unlikely to be stabilized by n → π* interactions.…”

Thermodynamics of Ligand-Protein Interactions: Implications for Molecular Design

“…Only recently it received attention in the field of medicinal chemistry and ligand-protein interactions (Paulini et al, 2005), even though it has been described for a long time. This interaction is known to contribute to ligand-protein stabilisation (Fischer et al, 2008), and it is particularly important in the context of halogen bonds (Bissantz et al, 2010 and references therein). It is worth bearing in mind that in an orthogonal (perpendicular) orientation of two dipoles, the actual dipole contribution to interaction energy is zero.…”