Chemical double-mutant cycles: dissecting non-covalent interactions

Cockroft, Scott L.; Hunter, Christopher A.

doi:10.1039/b603842p

Cited by 266 publications

(220 citation statements)

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“…for review see [8,11,24,34,36,37,227]). The problem of 'energetic composition' of π-stacking is, however, currently far from solution, which is, in part, due to the fundamental ambiguity of thermodynamic analysis (to be discussed below), making a great challenge for further studies.…”

Section: Energetics Of Hetero-associationmentioning

confidence: 99%

“…The hetero-association of specially selected (synthesised) aromatic molecules has been used as a model system to provide insight into various processes of particular importance in chemistry, such as 4 M.P. Evstigneev arrangement of nucleic acid bases derivatives in stacked complexes [23,30], binding of drugs to nucleic acids [31] and aromatic residues of proteins [32,33], protein-DNA and protein-protein interactions [3,34], exciton and charge-transfer interactions [25,34,35], dye chemistry [22], electrostatic complementarity [12,36], and 'energetic composition' of π-stacking [3,8,37]. (2) Biochemical applications.…”

Section: Applications Of Hetero-associationmentioning

confidence: 99%

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Hetero-association of aromatic molecules in aqueous solution

Evstigneev

2014

International Reviews in Physical Chemistry

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Knowledge of the physical chemistry of small molecules complexation (the hetero-association) in aqueous solution is increasingly important in view of the rapidly emerging branch of supramolecular chemistry dealing with the formation of heterogeneous polymeric structures having specific functional roles. In this paper, the 50-year history of scientific studies of hetero-association of heterocyclic aromatic molecules in aqueous solution has been reviewed. Some important correlations of structural and thermodynamic parameters of complexation have been reported based on large data-set of hetero-association parameters accumulated to date. The fundamental problem of 'energetic composition' of π-stacking is extensively discussed. The review has shown that there are some gaps in our understanding of heteroassociation, which provides a challenge for further studies in this area.

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Section: Energetics Of Hetero-associationmentioning

confidence: 99%

Section: Applications Of Hetero-associationmentioning

confidence: 99%

Hetero-association of aromatic molecules in aqueous solution

Evstigneev

2014

International Reviews in Physical Chemistry

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“…The primary noncovalent interaction, an aromatic-aromatic edge-to-face C-H⅐ ⅐ ⅐ contact, prearranges the functional groups bearing the interacting carbonyl groups rather than enforcing a discrete geometry. The incremental energetic contribution attributed to the orthogonal dipolar CϭO⅐ ⅐ ⅐CϭO contact is subsequently dissected from the primary interaction by applying a chemical double-mutant cycle approach popularized by Hunter and coworkers (17). The work presented herein details the design, the synthesis, and the evaluation of a set of indole-extended molecular torsion balances ((Ϯ)-1 to (Ϯ)-4 in Fig.…”

mentioning

confidence: 99%

Orthogonal dipolar interactions between amide carbonyl groups

Fischer

Wood

Allen

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

120

109

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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-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...

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“…In a number of supramolecular systems, free energies for the formation of specific electrostatic interactions have been found to scale linearly with σ p . 46,47 Consequently, the inverted-U trends observed here would suggest that either the 50 formation of hydrogen bonds and cation-π interactions is cooperative in this system, or that other interactions influenced by the 5-substituent of the indole contribute to the free energy of binding. Table 1, which assume noncompetitive binding of 1a-h and water to 2.…”

mentioning

confidence: 96%

“…Similar approaches have been used for the analysis of aromatic interactions 46,47 and were deemed pertinent in this (LT 2 ) lipid:tryptophan complexes, the free energy of association becomes more favorable in comparison to tryptophan (1c) as the 5-substituent becomes more electron withdrawing (Fig. 5).…”

mentioning

confidence: 99%

Free-energy relationships for the interactions of tryptophan with phosphocholines

2009

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Publisher's copyright statement:Additional information: Use policyThe full-text may be used and/or reproduced, and given to third parties in any format or medium, without prior permission or charge, for personal research or study, educational, or not-for-prot purposes provided that:• a full bibliographic reference is made to the original source • a link is made to the metadata record in DRO • the full-text is not changed in any way The full-text must not be sold in any format or medium without the formal permission of the copyright holders.Please consult the full DRO policy for further details. In membrane proteins and peptides, tryptophan exhibits a marked tendency to occur in locations that correspond to the interfacial region of the lipid bilayer. The relative contributions of electrostatic, dipolar, hydrophobic and conformational effects on the interactions of tryptophan with lipids have been the subject of much speculation. In order to elucidate the fundamental 10 properties of tryptophan-phosphocholine interactions in the absence of competing factors such as protein conformation and membrane perturbation, we have determined the binding characteristics of a homologous series of tryptophan analogues to 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) in deuterochloroform using NMR titrimetric approaches. The data are analysed using a binding model that includes lipid aggregation and the explicit association of water with the lipid. 15For a series of substituents (OMe, Me, H, F, Cl, Br, I, NO 2 ) at the 5-position of the indole ring, the trends in the free energy of association for the formation of 1:1 and 1:2 lipid:tryptophan adducts both follow an inverted-U relationship as a function of the corresponding para-Hammett parameter, with tryptophan (R = H) exhibiting the weakest binding. These trends are shown to be consistent with participation of the indole side chain in both hydrogen bonds and cation-π interactions. 20Molecular dynamics simulations of tryptophan and DMPC in an explicit chloroform solvent model demonstrate that for the formation of lipid-tryptophan adducts, binding is driven predominantly by carbonyl-cation and cation-π interactions with the choline ammonium group, alongside hydrogen bonding interactions with the lipid phosphate. Some of these interactions operate co-operatively, which may account for the observed trends in free energy.

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Chemical double-mutant cycles: dissecting non-covalent interactions

Cited by 266 publications

References 69 publications

Hetero-association of aromatic molecules in aqueous solution

Hetero-association of aromatic molecules in aqueous solution

Orthogonal dipolar interactions between amide carbonyl groups

Free-energy relationships for the interactions of tryptophan with phosphocholines

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