For the Sequence YKGQ, the Turn and Extended Conformational Forms Are Separated by Small Barriers and the Turn Propensity Persists Even at High Temperatures: Implications for Protein Folding

Kaur, Harpreet; Sasidhar, Yellamraju U.

doi:10.1021/jp210227s

Cited by 12 publications

(13 citation statements)

References 76 publications

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“…This observation indicates that the population of turn conformations might not be very temperature dependent, in agreement with recent theoretical predictions and experimental results. 83, 91 For the C-terminal residue, we obtained pPII fractions of 0.67, 0.60, for cationic and zwitterionic AAA, respectively.…”

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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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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“…This is a very surprising result since one would naively expect that turn‐like structures are entropically disfavored and therefore less likely to be populated at higher temperatures. However, a recent computational study aimed at exploring the behavior of the YKGQ sequence in a hairpin‐forming peptide found that it can form turns at low (room) as well as at high temperature because enthalpy and entropy are both stabilizing 66…”

Section: Resultsmentioning

confidence: 99%

Disorder and order in unfolded and disordered peptides and proteins: A view derived from tripeptide conformational analysis. II. Tripeptides with short side chains populating asx and β‐type like turn conformations

Rybka¹,

Toal²,

Verbaro³

et al. 2013

Proteins

124

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In the preceding paper, we found that ensembles of tripeptides with long or bulky chains can include up to 20% of various turns. Here, we determine the structural and thermodynamic characteristics of GxG peptides with short polar and/or ionizable central residues (D, N, C), whose conformational distributions exhibit higher than average percentage (>20%) of turn conformations. To probe the side-chain conformations of these peptides, we determined the (3)J(H(α),H(β)) coupling constants and derived the population of three rotamers with χ1 -angles of -60°, 180° and 60°, which were correlated with residue propensities by DFT-calculations. For protonated GDG, the rotamer distribution provides additional evidence for asx-turns. A comparison of vibrational spectra and NMR coupling constants of protonated GDG, ionized GDG, and the protonated aspartic acid dipeptide revealed that side chain protonation increases the pPII content at the expense of turn populations. The charged terminal groups, however, have negligible influence on the conformational properties of the central residue. Like protonated GDG, cationic GCG samples asx-turns to a significant extent. The temperature dependence of the UVCD spectra and (3)J(H(N)H(α)) constants suggest that the turn populations of GDG and GNG are practically temperature-independent, indicating enthalpic and entropic stabilization. The temperature-independent J-coupling and UVCD spectra of GNG require a three-state model. Our results indicate that short side chains with hydrogen bonding capability in GxG segments of proteins may serve as hinge regions for establishing compact structures of unfolded proteins and peptides.

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“…The values for Δ G ( T R ) were calculated from the pPII/β mole fraction ratio obtained from the conformational analysis . Eqn is based on the experimentally backed assumption that even in the presence of multiple conformers, the temperature dependence of the Gibbs energy landscape can practically be accounted for by a two‐state model, which assumes that the population of minor turn fractions does not change with temperature …”

Section: Methodsmentioning

confidence: 99%

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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For the Sequence YKGQ, the Turn and Extended Conformational Forms Are Separated by Small Barriers and the Turn Propensity Persists Even at High Temperatures: Implications for Protein Folding

Cited by 12 publications

References 76 publications

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

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

Disorder and order in unfolded and disordered peptides and proteins: A view derived from tripeptide conformational analysis. II. Tripeptides with short side chains populating asx and β‐type like turn conformations

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

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