Disorder and order in unfolded and disordered peptides and proteins: A view derived from tripeptide conformational analysis. I. Tripeptides with long and predominantly hydrophobic side chains

Schweitzer‐Stenner, Reinhard; Hagarman, Andrew; Toal, Siobhan; Mathieu, Daniel; Schwalbe, Harald

doi:10.1002/prot.24225

Cited by 37 publications

(133 citation statements)

References 63 publications

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“…valine (V), were found to be lower than reported by Grdadonik et al and Shi et al (0.32 vs 0.47 and 0.74, respectively). Moreover, the distributions reported by Hagarman et al reveal a diversity of possible β‐strand and to a more limited extent pPII sub‐distributions in terms of their position in the Ramachandran plot . All three studies fully agree in revealing A as the residue with the highest pPII propensity, which is in line with earlier predictions from the Kallenbach group and with distributions derived from truncated coil libraries .…”

Section: Introductionsupporting

confidence: 83%

“…However, the rather different temperature dependence of 3 J (H N H α ) (high for GHG + and practically absent for GHG ++ ) suggests that solvent‐mediated interactions between the protonated imidazole and the C‐terminal lead to reduced hydration of the peptide backbone, which practically eliminates the rather large enthalpic and entropic differences between pPII and β. Interestingly, Toal et al saw a similar effect for L and V in GxLG and GxVG peptides, respectively, if they replaced protonated D (for GxLG and GxVG) and serine (for GxVG) was chosen for x . Contrary to H + , L and V are purely aliphatic but share with H + a rather high propensity of β‐strand and overall a very balanced pPII/β‐partition . It seems that this property combined with polar groups in close proximity can induce rather substantial changes of the peptide's hydration.…”

Section: Discussionmentioning

confidence: 96%

“…The possibility of the population of turn like conformation had to be ignored because the experimental data did not provide the necessary information. This issue was first addressed by Hagarman et al , who combined FT‐infrared (IR), polarized Raman, vibrational circular dichroism (VCD) and NMR spectroscopy to elucidate conformational distributions of 15 cationic GxG peptides in water . Besides P and G, their set of peptides did not contain tryptophan, glutamine and histidine.…”

Section: Introductionmentioning

confidence: 99%

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Probing conformational propensities of histidine in different protonation states of the unblocked glycyl‐histidyl‐glycine peptide by vibrational and NMR spectroscopy

DiGuiseppi

Schweitzer‐Stenner

2016

J Raman Spectroscopy

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Histidine has been shown to play a major role in a number of biological systems. Being able to understand unconstrained conformational distributions of histidine and their dependence on the environment can shed light on the structure–function relation with regard to its multiple roles in biochemical processes such as proton transfer, ligand binding, protein folding and maintaining protein intrinsic disorder. We utilized polarized Raman, FTIR, vibrational circular dichroism and 1H NMR spectroscopy to probe the conformational distribution of the central histidine in the unblocked tripeptide H‐Gly‐His‐Gly‐OH in D2O. Our results show that in the double protonated state (GHG++), 94% of the histidine residue resides in the upper left quadrant of the Ramachandran plot with an equal partition between polyproline II (pPII) and β‐strand conformations. In this protonation state, enthalpic and entropic differences between the two conformations are practically eliminated, which indicates reduced backbone and/or side chain hydration. On the contrary, the single protonated state (GHG+), while only marginally different with regard to the pPII/β partition at room temperature (β‐strand is now slightly favored), shows an enthalpic stabilization of pPII by 43.02 kJ/mol, which is being compensated by an entropic stabilization of β‐strand (0.145 kJ/(mol K)). This indicates a much stronger coupling between peptide and water. At neutral pH, where the imidazole side chain of the histidine residue is deprotonated, GHG in D2O forms a hydrogel above a peptide concentration of approximately 25 mm. Some experimental evidence suggests that the preceding peptide aggregation involves hydrogen bonding between the C‐terminal groups and the imidazole NH group. Copyright © 2016 John Wiley & Sons, Ltd.

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Section: Introductionsupporting

confidence: 83%

Section: Discussionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

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Probing conformational propensities of histidine in different protonation states of the unblocked glycyl‐histidyl‐glycine peptide by vibrational and NMR spectroscopy

DiGuiseppi

Schweitzer‐Stenner

2016

J Raman Spectroscopy

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“…In this context alanine stands out by exhibiting an above‐the‐average propensity for pPII conformations which are associated with the region around ( ϕ , ψ )=(−75°, 150°) in the Ramachandran plot. On the contrary, residues with hydrophobic and bulky side chains like valine or isoleucine prefer a more extended β‐strand‐like conformation over pPII 4c,g,i,j,o. 5 Interestingly, the polar protonated aspartic acid residue exhibits the largest β‐strand‐to‐pPII ratio, which might reflect stabilization by side chain–backbone hydrogen bonding 4k,n.…”

Section: Introductionmentioning

confidence: 99%

Randomizing the Unfolded State of Peptides (and Proteins) by Nearest Neighbor Interactions between Unlike Residues

Toal

Kubatova

Richter

et al. 2015

Chemistry A European J

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To explore the influence of nearest neighbors on conformational biases in unfolded peptides, we combined vibrational and 2D NMR spectroscopy to obtain the conformational distributions of selected "GxyG" host-guest peptides in aqueous solution: GDyG, GSyG, GxLG, GxVG, where x/y=A, K, L, V. Large changes of conformational propensities were observed due to nearest-neighbor interactions, at variance with the isolated pair hypothesis. We found that protonated aspartic acid and serine lose their above-the-average preference for turn-like structures in favor of polyproline II (pPII) populations in the presence of neighbors with bulky side chains. Such residues also decrease the above-the-average pPII preference of alanine. These observations suggest that the underlying mechanism involves a disruption of the hydration shell. Thermodynamic analysis of (3) J(H(N) ,H(α) ) (T) data for each x,y residue reveals that modest changes in the conformational ensemble masks larger changes of enthalpy and entropy governing the pPII↔β equilibrium indicating a significant residue dependent temperature dependence of the peptides' conformational ensembles. These results suggest that nearest-neighbor interactions between unlike residues act as conformational randomizers close to the enthalpy-entropy compensation temperature, eliminating intrinsic biases in favor of largely balanced pPII/β dominated ensembles at physiological temperatures.

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“…The statistical significance of such weakly populated conformations has recently been discussed in another publication from our group. 79 …”

Section: Resultsmentioning

confidence: 99%

pH-Independence of Trialanine and the Effects of Termini Blocking in Short Peptides: A Combined Vibrational, NMR, UVCD, and Molecular Dynamics Study

et al. 2013

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Several lines of evidence now well establish that unfolded peptides in general, and alanine in specific, have an intrinsic preference for the polyproline II (pPII) conformation. Investigation of local order in the unfolded state is, however, complicated by experimental limitations and the inherent dynamics of the system, which has in some cases yielded inconsistent results from different types of experiments. One method of studying these systems is the use of short model peptides, and specifically short alanine peptides, known for predominantly sampling pPII structure in aqueous solution. Recently, He et al. (J. Am. Chem. Soc. 2012, 134, 1571–1576) proposed that unblocked tripeptides may not be suitable models for studying conformational propensities in unfolded peptides due to the presence of end effect, i.e. electrostatic interactions between investigated amino acid residues and terminal charges. To determine whether changing the protonation states of the N- and C-termini influence the conformational manifold of the central amino acid residue in tripeptides, we have examined the pH-dependence of unblocked trialanine and the conformational preferences of alanine in the alanine dipeptide. To this end, we measured and globally analyzed amide I’ band profiles and NMR J-coupling constants. We described conformational distributions as the superposition of two-dimensional Gaussian distributions assignable to specific sub-spaces of the Ramachandran plot. Results show that the conformational ensemble of trialanine as a whole, and the pPII content (χpPII=0.84) in particular, remain practically unaffected by changing the protonation state. We found that compared to trialanine, the alanine dipeptide has slightly lower pPII content (χpPII=0.74) and an ensemble more reminiscent of the unblocked Gly-Ala-Gly model peptide. In addition, a two-state thermodynamic analysis of the conformational sensitive Δε(T) and 3J(HNHα)(T) data obtained from electronic circular dichroism and H-NMR spectra indicate that the free energy landscape of trialanine is similar in all protonation states. MD simulations for the investigated peptides corroborate this notion and show further that the hydration shell around unblocked trialanine is unaffected by the protonation/deprotonation of the C-terminal group. In contrast, the alanine dipeptide shows a reduced water density around the central residue as well as a less ordered hydration shell, which decreases the pPII propensity and reduces the lifetime of sampled conformations.

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Disorder and order in unfolded and disordered peptides and proteins: A view derived from tripeptide conformational analysis. I. Tripeptides with long and predominantly hydrophobic side chains

Cited by 37 publications

References 63 publications

Probing conformational propensities of histidine in different protonation states of the unblocked glycyl‐histidyl‐glycine peptide by vibrational and NMR spectroscopy

Probing conformational propensities of histidine in different protonation states of the unblocked glycyl‐histidyl‐glycine peptide by vibrational and NMR spectroscopy

Randomizing the Unfolded State of Peptides (and Proteins) by Nearest Neighbor Interactions between Unlike Residues

pH-Independence of Trialanine and the Effects of Termini Blocking in Short Peptides: A Combined Vibrational, NMR, UVCD, and Molecular Dynamics Study

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