Orthogonal Multipolar Interactions in Structural Chemistry and Biology

Paulini, Ralph; Mueller, Klaus A.; Diederich, François

doi:10.1002/chin.200525294

Cited by 63 publications

(100 citation statements)

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“…Thus, to avoid close contacts between F2′ and sugar, base, and probably also the backbone portion (O5′) of the adjacent nucleotide, the latter is pushed away, requiring it to flip into a C2′-endo conformation. The existence of short orthogonal interactions between fluorine and electrophilic centers (i.e., nitrile or amide carbon) has been pointed out (reviewed in ref 61), and they can be expected to contribute favorably to stability. However, we believe it to be unlikely that close contacts between F2′ and C8 (shorter than 3 Å in three of four cases; Figure 5B) add much in terms of stability.…”

Section: Resultsmentioning

confidence: 99%

2‘-Fluoroarabino- and Arabinonucleic Acid Show Different Conformations, Resulting in Deviating RNA Affinities and Processing of Their Heteroduplexes with RNA by RNase H^,

Sarkhel

Wilds

et al. 2006

Biochemistry

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2′-Deoxy-2′-fluoro-arabinonucleic acid (FANA) and arabinonucleic acid (ANA) paired to RNA are substrates of RNase H. The conformation of the natural DNA/RNA hybrid substrates appears to be neither A-form nor B-form. Consistent with this, the conformations of FANA and ANA were found to be intermediate between the A-and B-forms. However, FANA opposite RNA is preferred by RNase H over ANA, and the RNA affinity of FANA considerably exceeds that of ANA. By investigating the conformational boundaries of FANA and ANA residues in crystal structures of A-and B-form DNA duplexes at atomic resolution, we demonstrate that FANA and ANA display subtle conformational differences. The structural data provide insight into the structural requirements at the catalytic site of RNase H. They also allow conclusions with regard to the relative importance of stereoelectronic effects and hydration as modulators of RNA affinity.

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Section: Resultsmentioning

confidence: 99%

2‘-Fluoroarabino- and Arabinonucleic Acid Show Different Conformations, Resulting in Deviating RNA Affinities and Processing of Their Heteroduplexes with RNA by RNase H^,

Sarkhel

Wilds

et al. 2006

Biochemistry

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“…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.…”

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confidence: 99%

Orthogonal dipolar interactions between amide carbonyl groups

Fischer

Wood

Allen

et al. 2008

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

119

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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“…These interactions are formed by two dipolar functional groups, which are in a close distance from each other. 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).…”

Section: Halogen Bonds and Multipolar Interactionsmentioning

confidence: 99%

Thermodynamics of Ligand-Protein Interactions: Implications for Molecular Design

Bronowska¹

2011

Thermodynamics - Interaction Studies - Solids, Liquids and Gases

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Orthogonal Multipolar Interactions in Structural Chemistry and Biology

Abstract: For Abstract see ChemInform Abstract in Full Text.

Cited by 63 publications

References 1 publication

2‘-Fluoroarabino- and Arabinonucleic Acid Show Different Conformations, Resulting in Deviating RNA Affinities and Processing of Their Heteroduplexes with RNA by RNase H^,

2‘-Fluoroarabino- and Arabinonucleic Acid Show Different Conformations, Resulting in Deviating RNA Affinities and Processing of Their Heteroduplexes with RNA by RNase H^,

Orthogonal dipolar interactions between amide carbonyl groups

Thermodynamics of Ligand-Protein Interactions: Implications for Molecular Design

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Orthogonal Multipolar Interactions in Structural Chemistry and Biology

Abstract: For Abstract see ChemInform Abstract in Full Text.

Cited by 63 publications

References 1 publication

2‘-Fluoroarabino- and Arabinonucleic Acid Show Different Conformations, Resulting in Deviating RNA Affinities and Processing of Their Heteroduplexes with RNA by RNase H,

2‘-Fluoroarabino- and Arabinonucleic Acid Show Different Conformations, Resulting in Deviating RNA Affinities and Processing of Their Heteroduplexes with RNA by RNase H,

Orthogonal dipolar interactions between amide carbonyl groups

Thermodynamics of Ligand-Protein Interactions: Implications for Molecular Design

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Product

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2‘-Fluoroarabino- and Arabinonucleic Acid Show Different Conformations, Resulting in Deviating RNA Affinities and Processing of Their Heteroduplexes with RNA by RNase H^,

2‘-Fluoroarabino- and Arabinonucleic Acid Show Different Conformations, Resulting in Deviating RNA Affinities and Processing of Their Heteroduplexes with RNA by RNase H^,