Local Backbone Preferences and Nearest‐Neighbor Effects in the Unfolded and Native States

DeBartolo, Joe; Jha, Abhishek; Freed, Karl F.; Sosnick, Tobin R.

doi:10.1002/9781118183373.ch3

Cited by 15 publications

(31 citation statements)

References 85 publications

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“…Previous studies by us4j,k,n,o, 7d, 13, 14 and others4c,g,l,m, 5a,b, 10b, 15 have clearly shown that, within the unfolded state, amino acid residues have unique and restricted conformational biases. Here we examine the mutual effect of unlike residues (x and y, Table 1) on residue‐level conformational bias through a combined analysis of vibrational and NMR results for GxyG peptide motifs.…”

Section: Resultsmentioning

confidence: 87%

“…exhibit an above‐the‐average sampling of turn‐like conformations, which includes conformations found in various types of β‐turns and so‐called asx‐turns, which are located in the upper‐right quadrant of the Ramachandran plot 4k,n. 6 Second, the analysis of coil libraries and results of computations provided strong evidence for the notion that the IPH is invalid because conformational propensity of a residue depends on the physicochemical properties and the conformation of its neighbors 4m. 6a, 7 Third, non‐local interactions stabilize more compact tertiary and sporadically also regular secondary structures 8.…”

Section: Introductionmentioning

confidence: 99%

“…For instance, Sosnick and associates examined the conformational distributions of residues obtained by analysis of restricted coil libraries (i.e., all stable structures eliminated) as a function of NN identity 2a. 4f,m, 10 To increase the sampling size of the library while retaining the dominant steric effects, Jha et al. separated NNs into three classes according to the main steric properties of their side chains: 1) β‐branched side chains (V, I, and T); 2) aromatic side chains (W, F, Y, and H); and 3) the remaining called alanine‐like (except G and P) 4f.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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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Section: Resultsmentioning

confidence: 87%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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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show abstract

“…17-19 Over the last twenty years, however, multiple experimental, and in part even theoretical, evidence has been provided for the notion that the conformational space of most amino acid residues is much more restricted than suggested by the random coil model. 3-5, 10-12, 20-22 Moreover, it has become clear that amino acid residues show different conformational distributions, which can be altered by the nearest neighbors. 3, 22-26 In this context, polyproline II (pPII) has emerged as the dominant conformation for alanine, 10 whereas the pPII propensity of other residues is still a matter of a controversial debate.…”

Section: Introductionmentioning

confidence: 99%

“…3-5, 10-12, 20-22 Moreover, it has become clear that amino acid residues show different conformational distributions, which can be altered by the nearest neighbors. 3, 22-26 In this context, polyproline II (pPII) has emerged as the dominant conformation for alanine, 10 whereas the pPII propensity of other residues is still a matter of a controversial debate. 3, 10, 11, 27 The canonical pPII conformation with (φ,ψ)=(−75°, 150°) is adopted by residues in trans -polyproline where it brings about a 3 1 -helix structure of the peptide.…”

Section: Introductionmentioning

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

Schweitzer‐Stenner¹,

Hagarman²,

Toal³

et al. 2013

Proteins

119

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We performed a conformational analysis of the central residues of three tripeptides glycyl-L-isoleucyl-glycine (GIG), glycyl-L-tyrosyl-glycine (GYG) and glycyl-L-arginyl-glycine (GRG) in aqueous solution, based on a global analysis of amide I' band profiles and NMR J-coupling constants. The results are compared with recently reported distributions of GVG, GFG and GEG. For GIG and GYG, we found that even though the polyproline II (pPII) fraction is below 0.5, it is still the most populated conformation, whereas GVG and GFG show both a larger β-strand fraction. For GRG, we observed a clear dominance of pPII over β-strand, reminiscent of observations for GEG and GKG. This finding indicates that terminal charges on otherwise hydrophobic residue side chains stabilize pPII over β-strand conformations. For all peptides investigated we found that a variety of compact and turn-like conformations constitute nearly 20 percent of their conformational distributions. Attempts to analyze our data with a simple two-state pPII-->/<--β model therefore do not yield any satisfactory reproduction of experimental results. A comparison of the obtained GxG ensembles with conformational distributions of GxG segments in truncated coil libraries (helices and sheets omitted) revealed a much larger fraction of type II β(i+2) and type III β like conformations for the latter. Thus, a comparison of conformational distributions of unfolded peptide segments in solution and in coil libraries reveal interesting information on how the interplay between intrinsic propensities of amino acid residues and non-local interactions in polypeptide chains determine the conformations of loop segments in proteins.

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Local Backbone Preferences and Nearest‐Neighbor Effects in the Unfolded and Native States

Cited by 15 publications

References 85 publications

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

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

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

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