Direct Evidence for CH···π Interaction Mediated Stabilization of Pro-<i>cis</i>Pro Bond in Peptides with Pro-Pro-Aromatic motifs

Ganguly, Himal K.; Majumder, Barun; Chattopadhyay, S.; Chakrabarti, Pinak; Basu, Gautam

doi:10.1021/ja209334v

Cited by 47 publications

(96 citation statements)

References 49 publications

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“…The trends in ellipticity vs. temperature generally agreedw ith those observedf or proline-rich PPII helices, specifically that the mean residue ellipticity (MRE) values decreased as af unction of increasing temperature. [29] Nevertheless, we concluded that the thermal stabilities of PPII helices in structures featuring peptoid and proline mutants were similar.N otably,i ncorporation of peptoid residues in two sequences (cTp_XE and cTp_XP) did not diminish the stability of PPII helical structure, as both mutation sets appeared to slightly enhance the thermal stabilityo ft he helical positions. [29] Nevertheless, we concluded that the thermal stabilities of PPII helices in structures featuring peptoid and proline mutants were similar.N otably,i ncorporation of peptoid residues in two sequences (cTp_XE and cTp_XP) did not diminish the stability of PPII helical structure, as both mutation sets appeared to slightly enhance the thermal stabilityo ft he helical positions.…”

Section: Synthesis and Characterization Of Pxxp Mimetic Trpplexus Seqsupporting

confidence: 77%

“…[18] Units are in mean residue ellipticity (MRE, deg cm 2 dmol À1 res À1 ). [29,30] Therefore, in select cases such as the TrpPlexus fold, prolinec ompatibilityw ith the PPII helix is not guaranteed. B) Far-UVC Dt hermal melts monitoring meanresidue ellipticity at 228 nm as af unction of temperature for sequencese xhibiting PPII helical content(100 mm,1mm pathl ength, 10 mm PBS buffer, pH 7.5).…”

Section: Design Of Pxxp Mimetic Trpplexussequencesmentioning

confidence: 99%

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PPII Helical Peptidomimetics Templated by Cation–π Interactions

2016

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Poly-proline type II (PPII) helical PXXP motifs are the recognition elements for a variety of protein-protein interactions that are critical for cellular signaling. Despite development of protocols for locking peptides into α-helical and β-strand conformations, there remains a lack of analogous methods for generating mimics of PPII helical structures. We describe herein a strategy to enforce PPII helical secondary structure in the 19-residue TrpPlexus miniature protein. Through sequence variation, we showed that a network of cation-π interactions could drive the formation of PPII helical conformations for both peptide and N-substituted glycine peptoid residues. The achievement of chemically diverse PPII helical scaffolds provides a new route towards discovering peptidomimetic inhibitors of protein-protein interactions mediated by PXXP motifs.

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Section: Synthesis and Characterization Of Pxxp Mimetic Trpplexus Seqsupporting

confidence: 77%

Section: Design Of Pxxp Mimetic Trpplexussequencesmentioning

confidence: 99%

PPII Helical Peptidomimetics Templated by Cation–π Interactions

2016

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“…9–11,20,21,23,46 cis-Pro-Aromatic interactions can result from the aromatic ring interacting with the preceding proline ring, or from the aromatic ring interacting with Hα two residues prior to it (H α ( i −2)-cis-Pro-Aromatic( i ) interactions), which involves a cis prolyl amide bond (Figure 2). 1,6–8,20 Studies by Creighton and Basu indicated that cis-Pro-Aromatic interactions, primarily with H α ( i −2) of Gly or Pro two residues prior to Tyr/Trp/Phe, are enthalpically favorable and dependent on electronics of the aromatic residue.…”

Section: Local Aromatic-proline Interactionsmentioning

confidence: 99%

“…1,6–8,20 Studies by Creighton and Basu indicated that cis-Pro-Aromatic interactions, primarily with H α ( i −2) of Gly or Pro two residues prior to Tyr/Trp/Phe, are enthalpically favorable and dependent on electronics of the aromatic residue. 10,11,20,22,23 Aromatic-Pro-aromatic sequences also exhibit a high propensity for cis amide bonds, with aromatic rings able to stack against both faces of the proline ring. 8 Interestingly, Dyson and Wright found that in SYPXDV peptides, the highest population of cis amide bonds was observed with Phe, rather than Tyr or Trp, at the X position.…”

Section: Local Aromatic-proline Interactionsmentioning

confidence: 99%

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Aromatic–Proline Interactions: Electronically Tunable CH/π Interactions

2012

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CONSPECTUS Proline residues have unique roles in protein folding, structure, and function. Proline combined with the aromatic amino acids comprise the encoded cyclic protein residues. Aromatic protein side chains are defined by their negatively charged π faces, while the faces of the proline ring are partially positively charged. This polarity results from their two-point connection of the side chain to the electron-withdrawing protein backbone, and the lower electronegativity of hydrogen compared to carbon, nitrogen, and oxygen. The hydrogens adjacent to the carbonyl and amide nitrogen, Ha and Hδ, respectively, are the most partially positive. Proline’s side chain is also conformationally restricted, allowing for interaction with aromatic residues with minimal entropic or steric penalty. Proline and aromatic residues can interact favorably with each other, due to both the hydrophobic effect and the interaction between the π aromatic face and the polarized C-H bonds, called a CH/π interaction. Aromatic-proline interactions can occur locally, for example to stabilize cis-amide bonds, and over larger distances, in the tertiary structures of proteins, and intermolecularly in protein-protein interactions. In peptides and proteins, aromatic-proline sequences more readily adopt cis-prolyl amide bonds, where the aromatic ring interacts with the proline ring in the cis conformation. In aromatic-proline sequences, Trp and Tyr are more likely to induce cis-amide bonds than Phe, suggesting an aromatic electronic effect. This result would be expected for a CH/π interaction, in which a more electron-rich aromatic would have a stronger (more cis-stabilizing) interaction with partial positive charges on prolyl hydrogens. In this Account, we describe our investigations into the nature of local aromatic-proline interactions, using peptide models. We synthesized a series of 26 peptides, TXPN, varying X from electron-rich to electron poor aromatic amino acids, and found that the population of cis-amide bond (Ktrans/cis) is tunable by aromatic electronics. With 4-substituted phenylalanines, we observed a Hammett correlation between aromatic electronics and Ktrans/cis, with cis-trans isomerism electronically controllable by 1.0 kcal/mol. All aromatic residues exhibit a higher cis population than Ala or cyclohexylalanine, with Trp showing the strongest aromatic-proline interaction. In addition, proline stereoelectronic effects can modulate cis-trans isomerism by an additional 1.0 kcal/mol. The aromatic-proline interaction is enthalpic, consistent with its description as a CH/π interaction. Proline-aromatic sequences can also promote cis-prolyl bonds, either through interactions of the aromatic ring with the preceding cis-proline, or with the Hα prior to cis-proline. Within proline-rich peptides, sequences commonly found in natively disordered proteins, aromatic residues promote multiple cis-amide bonds due to multiple favorable aromatic-proline interactions. Collectively, we found aromatic-proline interactions to be significantly CH/...

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Type VIa β‐turn‐fused helix N‐termini: A novel helix N‐cap motif containing cis proline

et al. 2017

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Helix N-capping motifs often form hydrogen bonds with terminal amide groups which otherwise would be free. Also, without an amide hydrogen, proline (trans) is over-represented at helix N-termini (N1 position) because this naturally removes the need to hydrogen bond one terminal amide. However, the preference of cisPro, vis-à-vis helix N-termini, is not known. We show that cisPro (α or PP ) often appears at the N-cap position (N0) of helices. The N-cap cisPro(α ) is associated with a six-residue sequence motif - X -X -cisPro-X -X -X - with preference for Glu/Gln at X , Phe/Tyr/Trp at X and Ser/Thr at X . The motif, formed by the fusion of a helix and a type VIa β-turn, contains a hydrogen bond between the side chain of X and the side chain/backbone of X , a α-helical hydrogen bond between X and X and stacking interaction between cisPro and an aromatic residue at X . NMR experiments on peptides containing the motif and its variants showed that local interactions associated with the motif, as found in folded proteins, were not enough to significantly tilt the cis/trans equilibrium towards cisPro. This suggests that some other evolutionary pressure must select the cisPro motif (over transPro) at helix N-termini. Database analysis showed that >C = O of the pre-cisPro(α ) residue at the helix N-cap, directed opposite to the N→C helical axis, participates in long-range interactions. We hypothesize that the cisPro(α ) motif is preferred at helix N-termini because it allows the helix to participate in long-range interactions that may be structurally and functionally important.

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Direct Evidence for CH···π Interaction Mediated Stabilization of Pro-cisPro Bond in Peptides with Pro-Pro-Aromatic motifs

Cited by 47 publications

References 49 publications

PPII Helical Peptidomimetics Templated by Cation–π Interactions

PPII Helical Peptidomimetics Templated by Cation–π Interactions

Aromatic–Proline Interactions: Electronically Tunable CH/π Interactions

Type VIa β‐turn‐fused helix N‐termini: A novel helix N‐cap motif containing cis proline

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