Rabbit-ears hybrids, VSEPR sterics, and other orbital anachronisms

Clauss, Allen D.; Nelsen, Stephen F.; Ayoub, Mohamed; Moore, John W.; Landis, Clark R.; Weinhold, Frank

doi:10.1039/c4rp00057a

Cited by 60 publications

(63 citation statements)

References 51 publications

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“…This observation is consistent with a modern description of the carbonyl lone pairs, featuring a predominantly s -type orbital ( n s ) along the carbonyl bond with a p orbital ( n p ) in an orthogonal orientation (Fig. 1a,b) 6 . Whereas n s is poised to engage in common hydrogen-bond patterns in proteins, the role of n p is less clear.…”

supporting

confidence: 91%

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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supporting

confidence: 91%

A prevalent intraresidue hydrogen bond stabilizes proteins

2016

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“…64 The s -like orbital engages in an i → i + 4 hydrogen bond (Figure 7C), while the p -like orbital engages in an n →π* interaction (Figure 7D). When hydrogen-bond donors approach at ∼120° with respect to the carbonyl-bond axis, they encourage mixing of the s - and p -like orbitals, which then adopt the “rabbit ears” geometry that is all too familiar 65 to chemists.…”

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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“…[1 -3] This angle is the best to minimize lone pair repulsion and maximize hyperconjugation. [1] [2] In 3-alkyl-1,2-dithiolanes, the CXXC dihedral angle is 35°. [3] The opening of 1,2-dithiolanes 1 by dynamic-covalent thiolate-disulfide exchange with a thiolate 2 releases this ring tension.…”

mentioning

confidence: 99%

The Opening of 1,2‐Dithiolanes and 1,2‐Diselenolanes: Regioselectivity, Rearrangements, and Consequences for Poly(disulfide)s, Cellular Uptake and Pyruvate Dehydrogenase Complexes

Laurent

Sakai

Matile

2019

Helvetica Chimica Acta

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The thiol‐mediated opening of 3‐alkyl‐1,2‐dithiolanes and diselenolanes is described. The thiolate nucleophile is shown to react specifically with the secondary chalcogen atom, against steric demand, probably because the primary chalcogen atom provides a better leaving group. Once released, this primary chalcogen atom reacts with the obtained secondary dichalcogenide to produce the constitutional isomer. Thiolate migration to the primary dichalcogenide equilibrates within ca. 20 ms at room temperature at a 3 : 2 ratio in favor of the secondary dichalcogenide. The clarification of this focused question is important for the understanding of multifunctional poly(disulfide)s obtained by ring opening disulfide exchange polymerization of 3‐alkyl‐1,2‐dithiolanes, to rationalize the cellular uptake mediated by 3‐alkyl‐1,2‐diselenolanes as molecular walkers and, perhaps, also of the mode of action of pyruvate dehydrogenase complexes. The isolation of ring‐opened diselenolanes is particularly intriguing because dominant selenophilicity disfavors ring opening strongly.

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Rabbit-ears hybrids, VSEPR sterics, and other orbital anachronisms

Cited by 60 publications

References 51 publications

A prevalent intraresidue hydrogen bond stabilizes proteins

A prevalent intraresidue hydrogen bond stabilizes proteins

The n→π* Interaction

The Opening of 1,2‐Dithiolanes and 1,2‐Diselenolanes: Regioselectivity, Rearrangements, and Consequences for Poly(disulfide)s, Cellular Uptake and Pyruvate Dehydrogenase Complexes

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