Stereoelectronic effects on the transition barrier of polyproline conformational interconversion

Chiang, Yi-Chun; Lin, Yu-Ju; Horng, Jia‐Cherng

doi:10.1002/pro.208

Cited by 50 publications

(65 citation statements)

References 37 publications

(53 reference statements)

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“…Considering the conformational preferences of the amino acid monomers, the favored exo ring pucker of Flp enforced n→π* interactions between adjacent carbonyl groups, leading to increased populations of prolyl amide trans isomers and PPII helix. Subsequently, (4 R )- and (4 S )-fluoroprolines were shown to respectively increase and decrease the transition state barrier for PPII → PPI conversion [85]. This dichotomy was consistent with Flp stabilizing the prolyl amide trans isomer.…”

Section: Effects On Peptide Conformationmentioning

confidence: 79%

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

Newberry

Raines

2016

Topics in Heterocyclic Chemistry

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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.

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Section: Effects On Peptide Conformationmentioning

confidence: 79%

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

Newberry

Raines

2016

Topics in Heterocyclic Chemistry

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“…In recent years, these transitions have been investigated theoretically. [50–53] It will be interesting to see if theoretical calculations can capture the fundamental essence of the folding differences of these systems in different solvents.…”

Section: Discussionmentioning

confidence: 99%

Ion Mobility-Mass Spectrometry Reveals the Energetics of Intermediates that Guide Polyproline Folding

Shi

Holliday

Glover

et al. 2015

J. Am. Soc. Mass Spectrom.

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Proline favors trans-configured peptide bonds in native proteins. Although cis/trans configurations vary for non-native and unstructured states, solvent also influences these preferences. Water induces the all-cis right-handed polyproline-I (PPI) helix of polyproline to fold into the all-trans left-handed polyproline-II (PPII) helix. Our recent work has shown that this occurs via a sequential mechanism involving six resolved intermediates. Here, we use ion mobility-mass spectrometry to make the first detailed thermodynamic measurements of the folding intermediates, which inform us about how and why this transition occurs. It appears that early intermediates are energetically favorable due to hydration of the peptide backbone, while late intermediates are enthalpically unfavorable. However, folding continues, as the entropy of the system increases upon successive formation of each new structure. When PPII is immersed in 1-propanol, the PPII→PPI transition occurs, but this reaction occurs through a very different mechanism. Early on, the PPII population splits onto multiple pathways that eventually converge through a late intermediate that continues on to the folded PPI helix. Nearly every step is endothermic. Folding results from a stepwise increase in the disorder of the system, allowing a wide-scale search for a critical late intermediate. Overall, the data presented here allow us to establish the first experimentally-determined energy surface for biopolymer folding as a function of solution environment.

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“…Moreover, the presence of a strong n →π* interaction, enforced by 4 R -configured electron-withdrawing substituents, also increases the barrier to interconversion of PPI and PPII helices. 56 The n →π* interaction has been implicated further in the PPII structures of other sequences, 57−59 demonstrating its ability to control peptide conformation. Recently, Wennemers and co-workers determined the first high-resolution crystal structure of an oligoproline.…”

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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Stereoelectronic effects on the transition barrier of polyproline conformational interconversion

Cited by 50 publications

References 37 publications

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

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

Ion Mobility-Mass Spectrometry Reveals the Energetics of Intermediates that Guide Polyproline Folding

The n→π* Interaction

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