Substituted 2-Azabicyclo[2.1.1]hexanes as Constrained Proline Analogues:  Implications for Collagen Stability

Jenkins, Cara L.; Lin, Guoliang; Duo, Jingqi; Rapolu, Deepa; Guzei, Ilia A.; Raines, Ronald T.; Krow, Grant R.

doi:10.1021/jo049242y

Cited by 62 publications

(72 citation statements)

References 65 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Analogous results were obtained for prolines with 4-azido substituents. 17 Crystallographic and computational analyses, 12 microwave spectroscopy, 42 and experiments with methanoprolines 43,44 have since established that in the absence of complicating hydrogen bonds, the endo pucker of the pyrrolidine ring generally increases the distance between the donor oxygen and the acceptor carbon, leading to weaker n →π* interactions. These results explain the destabilization of collagen-mimetic peptides by proline residues with electron-withdrawing substituents at 4 S -configured centers in the Yaa position.…”

Section: Contributions To Protein Structurementioning

confidence: 99%

The n→π* Interaction

2017

Self Cite

View full text Add to dashboard Cite

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...

show abstract

Section: Contributions To Protein Structurementioning

confidence: 99%

The n→π* Interaction

2017

Self Cite

View full text Add to dashboard Cite

show abstract

“…They have been shown to be ubiquitous in proteins [43,46,47], particularly about proline residues, in which the pyrrolidine ring pre-organizes the neighboring carbonyl groups to favor the n→π* interaction [43]. Fluorination of C4 influences the pyrrolidine ring pucker and the main-chain dihedral angles in ways that have important consequences for the n→π* interaction [48]. Specifically, the distance between the oxygen–carbon donor–acceptor pair of the neighboring carbonyls is generally longer in the endo pucker, which leads to a weaker n→π* interaction [49].…”

Section: Conformational Analysismentioning

confidence: 99%

4-Fluoroprolines: Conformational Analysis and Effects on the Stability and Folding of Peptides and Proteins

Newberry

Raines

2016

Topics in Heterocyclic Chemistry

Self Cite

View full text Add to dashboard Cite

Proline is unique among proteinogenic amino acids because a pyrrolidine ring links its amino group to its side chain. This heterocycle constrains the conformations of the main chain and thus templates particular secondary structures. Proline residues undergo post-translational modification at the 4-position to yield 4-hydroxyproline, which is especially prevalent in collagen. Interest in characterizing the effects of this modification led to the use of 4-fluoroprolines to enhance inductive properties relative to the hydroxyl group of 4-hydroxyproline and to eliminate contributions from hydrogen bonding. The strong inductive effect of the fluoro group has three main consequences: enforcing a particular pucker upon the pyrrolidine ring, biasing the conformation of the preceding peptide bond, and accelerating cis/trans prolyl peptide bond isomerization. These subtle, yet reliable modulations make 4-fluoroproline–incorporation a complement to traditional genetic approaches for exploring structure–function relationships in peptides and proteins, as well as for endowing peptides and proteins with conformational stability.

show abstract

“…The structure determinations were performed as described previously. 35,36 The experimental procedures and tables of atomic coordinates, bond lengths, bond angles, and torsion angles are provided in the Supporting Information.…”

Section: X-ray Crystallographymentioning

confidence: 99%

O‐acylation of hydroxyproline residues: Effect on peptide‐bond isomerization and collagen stability

et al. 2004

Self Cite

View full text Add to dashboard Cite

In collagen, strands of the sequence XaaYaaGly form a triple‐helical structure. The Yaa residue is often (2S,4R)‐4‐hydroxyproline (Hyp). The inductive effect of the hydroxyl group of Hyp residues greatly increases collagen stability. Here, electron withdrawal by the hydroxyl group in Hyp and its 4S diastereomer (hyp) is increased by the addition of an acetyl group or trifluoroacetyl group. The crystalline structures of AcHyp[C(O)CH3]OMe and Achyp[C(O)CH3]OMe are similar to those of AcHypOMe and AcProOMe, respectively. The O‐acylation of AcHypOMe and AchypOMe increases the 13C chemical shift of its Cγ atom: AcHyp[C(O)CF3]OMe ≅ Achyp[C(O)CF3]OMe > AcHyp[C(O)CH3]OMe ≅ Achyp[C(O)CH3]OMe ≥ AcHypOMe ≅ AchypOMe. This increased inductive effect is not apparent in the thermodynamics or kinetics of amide bond isomerization. Despite apparently unfavorable steric interactions, (ProHypGly)10, which is O‐acylated with 10 acetyl groups, forms a triple helix that has intermediate stability: (ProHypGly)10 > {ProHyp[C(O)CH3]Gly}10 ≫ (ProProGly)10. Thus, the benefit to collagen stability endowed by the hydroxyl group of Hyp residues is largely retained by an acetoxyl group. © 2004 Wiley Periodicals, Inc. Biopolymers (Pept Sci), 2005

show abstract

Substituted 2-Azabicyclo[2.1.1]hexanes as Constrained Proline Analogues: Implications for Collagen Stability

Cited by 62 publications

References 65 publications

The n→π* Interaction

The n→π* Interaction

4-Fluoroprolines: Conformational Analysis and Effects on the Stability and Folding of Peptides and Proteins

O‐acylation of hydroxyproline residues: Effect on peptide‐bond isomerization and collagen stability

Contact Info

Product

Resources

About