On the satisfaction of backbone‐carbonyl lone pairs of electrons in protein structures

Bartlett, Gail J.; Woolfson, Derek N.

doi:10.1002/pro.2896

Cited by 27 publications

(35 citation statements)

References 59 publications

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“…63 This concurrence creates interplay between these two interactions. The geometry of a hydrogen bond to an n →π* donor affects the ensuing n →π* interaction by controlling the demixing of the carbonyl lone pairs.…”

Section: Contributions To Protein Structurementioning

confidence: 99%

The n→π* Interaction

2017

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ConspectusThe carbonyl group holds a prominent position in chemistry and biology not only because it allows diverse transformations but also because it supports key intermolecular interactions, including hydrogen bonding. More recently, carbonyl groups have been found to interact with a variety of nucleophiles, including other carbonyl groups, in what we have termed an n→π* interaction. In an n→π* interaction, a nucleophile donates lone-pair (n) electron density into the empty π* orbital of a nearby carbonyl group. Mixing of these orbitals releases energy, resulting in an attractive interaction. Hints of such interactions were evident in small-molecule crystal structures as early as the 1970s, but not until 2001 was the role of such interactions articulated clearly.These non-covalent interactions were first discovered during investigations into the thermostability of the proline-rich protein collagen, which achieves a robust structure despite a relatively low potential for hydrogen bonding. It was found that by modulating the distance between two carbonyl groups in the peptide backbone, one could alter the conformational preferences of a peptide bond to proline. Specifically, only the trans conformation of a peptide bond to proline allows for an attractive interaction with an adjacent carbonyl group, so when one increases the proximity of the two carbonyl groups, one enhances their interaction and promotes the trans conformation of the peptide bond, which increases the thermostability of collagen.More recently, attention has been paid to the nature of these interactions. Some have argued that rather than resulting from electron donation, carbonyl interactions are a particular example of dipolar interactions that are well-approximated by classical mechanics. However, experimental evidence has demonstrated otherwise. Numerous examples now exist where an increase in the dipole moment of a carbonyl group decreases the strength of its interactions with other carbonyl groups, demonstrating unequivocally that a dipolar mechanism is insufficient to describe these interactions. Rather, these interactions have important quantum-mechanical character that can be evaluated through careful experimental analysis and judicious use of computation.Although individual n→π* interactions are relatively weak (∼0.3–0.7 kcal/mol), the ubiquity of carbonyl groups across chemistry and biology gives the n→π* interaction broad impact. In particular, the n→π* interaction is likely to play an important role in dictating protein structure. Indeed, bioinformatics analysis suggests that approximately one-third of residues in folded proteins satisfy the geometric requirements to engage in an n→π* interaction, which is likely to be of particular importance for the α-helix. Other carbonyl-dense polymeric materials like polyesters and peptoids are also influenced by n→π* interactions, as are a variety of small molecules, some with particular medicinal importance. Research will continue to identify molecules whose conformation and activity are affect...

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Section: Contributions To Protein Structurementioning

confidence: 99%

The n→π* Interaction

2017

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“…In an α-helix, the π* orbital of an adjacent carbonyl group can accept lone pair electron density from n p , forming a so-called n → π* interaction 7 ; however, adjacent carbonyl groups in β-sheets are too distil to accept electron density from n p . Moreover, whereas most backbone carbonyl groups in proteins can form two noncovalent interactions, one for each lone pair, the majority of backbone carbonyls that form only a single interaction are found in β-sheets 8 , suggesting that we might not yet appreciate all of the interactions present in this latter secondary structure. We therefore inquired as to what other electron acceptors could potentially engage with the carbonyl p -type lone pair in β-sheets.…”

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confidence: 99%

A prevalent intraresidue hydrogen bond stabilizes proteins

2016

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Current limitations in de novo protein structure prediction and design suggest an incomplete understanding of the interactions that govern protein folding. Here we demonstrate that previously unappreciated hydrogen bonds occur within proteins between the amide proton and carbonyl oxygen of the same residue. Quantum calculations, infrared spectroscopy, and nuclear magnetic resonance spectroscopy show that these interactions share hallmark features of canonical hydrogen bonds. Biophysical analyses demonstrate that selective attenuation or enhancement of these C5 hydrogen bonds affects the stability of synthetic β-sheets. These interactions are common, affecting approximately 5% of all residues and 94% of proteins, and their cumulative impact provides several kcal/mol of conformational stability to a typical protein. C5 hydrogen bonds stabilize, especially, the flat β-sheets of the amyloid state, which is linked with Alzheimer’s disease and other neurodegenerative disorders. Inclusion of these interactions in computational force fields would improve models of protein folding, function, and dysfunction.

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“…4 In an n → π* interaction, lone pair ( n ) electron density from a carbonyl oxygen is donated into the π* antibonding orbital of an adjacent carbonyl group, 5 thereby releasing upwards of 0.27 kcal/mol of stabilizing energy. 6 These interactions are particularly prevalent in α-helices, 7 where over 70% of adjacent residues are poised to engage in n → π* interactions 4a along with the canonical hydrogen bond within the main chain. 8 In the α-helix, a carbonyl oxygen donates electron density to two different acceptors.…”

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confidence: 99%

n→π* Interactions Are Competitive with Hydrogen Bonds

2016

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Because carbonyl groups can participate in both hydrogen bonds and n→π* interactions, these two interactions likely affect one another. Herein, enhancement of an amidic n→π* interaction is shown to reduce the ability of β-keto amides to tautomerize to the enol, indicating decreased hydrogen-bonding capacity of the amide carbonyl group. Thus, an n→π* interaction can have a significant effect on the strength of a hydrogen bond to the same carbonyl group.

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On the satisfaction of backbone‐carbonyl lone pairs of electrons in protein structures

Cited by 27 publications

References 59 publications

The n→π* Interaction

The n→π* Interaction

A prevalent intraresidue hydrogen bond stabilizes proteins

n→π* Interactions Are Competitive with Hydrogen Bonds

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