Local Order in the Unfolded State: Conformational Biases and Nearest Neighbor Interactions

Toal, Siobhan; Schweitzer‐Stenner, Reinhard

doi:10.3390/biom4030725

Cited by 57 publications

(70 citation statements)

References 195 publications

(375 reference statements)

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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: 86%

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: 86%

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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“…The situation for Δ G ( φ , ψ ) for disaccharides from the PG linker tetrasaccharide is in strong contrast to that for amino acid dipeptides, with a single prominent global minimum as described in the previous section. Therefore, the complete tetrasaccharide is expected to have a single predominant backbone conformation, unlike the situation for short peptides, which are known to have fluctuating backbone conformations . Indeed results of triplicate 1‐us standard all‐atom explicit‐solvent MD on both the GlcA and IdoA variants of the tetrasaccharide conjugated to serine dipeptide confirm this.…”

Section: Resultsmentioning

confidence: 86%

Rigidity and flexibility in the tetrasaccharide linker of proteoglycans from atomic‐resolution molecular simulation

Premnath

Guvench

2017

J Comput Chem

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Proteoglycans (PGs) are covalent conjugates between protein and carbohydrate (glycosaminoglycans). Certain classes of glycosaminoglycans such as chondroitin sulfate/dermatan sulfate and heparan sulfate utilize a specific tetrasaccharide linker for attachment to the protein component: GlcAβ1-3Galβ1-3Galβ1-4Xylβ1-O-Ser. Toward understanding the conformational preferences of this linker, the present work used all-atom explicit-solvent molecular dynamics (MD) simulations combined with Adaptive Biasing Force (ABF) sampling to determine high-resolution, high-precision conformational free energy maps ΔG(φ, ψ) for each glycosidic linkage between constituent disaccharides, including the variant where GlcA is substituted with IdoA. These linkages are characterized by single, predominant (> 97% occupancy), and broad (45° × 60° for ΔG(φ, ψ) < 1 kcal/mol) free-energy minima, while the Xyl-Ser linkage has two such minima similar in free-energy, and additional flexibility from the Ser sidechain dihedral. Conformational analysis of microsecond-scale standard MD on the complete tetrasaccharide-O-Ser conjugate is consistent with ABF data, suggesting (φ, ψ) probabilities are independent of the linker context, and that the tetrasaccharide acts as a relatively rigid unit whereas significant conformational heterogeneity exists with respect to rotation about bonds connecting Xyl to Ser. © 2017 Wiley Periodicals, Inc.

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“…The unfolded CD spectrum is typical of what is observed in other proteins upon thermal denaturation. Although often termed "random coil," this state represents an ensemble of backbone geometries with the (ϕ,ψ) dihedral angles predominantly in the PP2 basin and lesser populations in the α R , α L , and β basins (13)(14)(15)(16).…”

Section: Resultsmentioning

confidence: 99%

Perplexing cooperative folding and stability of a low-sequence complexity, polyproline 2 protein lacking a hydrophobic core

Gates

Baxa

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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The burial of hydrophobic side chains in a protein core generally is thought to be the major ingredient for stable, cooperative folding. Here, we show that, for the snow flea antifreeze protein (sfAFP), stability and cooperativity can occur without a hydrophobic core, and without α-helices or β-sheets. sfAFP has low sequence complexity with 46% glycine and an interior filled only with backbone H-bonds between six polyproline 2 (PP2) helices. However, the protein folds in a kinetically two-state manner and is moderately stable at room temperature. We believe that a major part of the stability arises from the unusual match between residue-level PP2 dihedral angle bias in the unfolded state and PP2 helical structure in the native state. Additional stabilizing factors that compensate for the dearth of hydrophobic burial include shorter and stronger H-bonds, and increased entropy in the folded state. These results extend our understanding of the origins of cooperativity and stability in protein folding, including the balance between solvent and polypeptide chain entropies.protein folding | cooperativity | kinetics | PP2 | hydrogen bonding T he basis of protein-folding stability and cooperativity remains a topic of great interest (1, 2). Most studies have focused on proteins with hydrophobic cores containing α-helices and β-sheets. Here, we study the folding of snow flea antifreeze protein (sfAFP), a globular protein that lacks these features. The 81-residue protein has a novel fold that is distinct from other proteins (3-6), containing only polyproline 2 (PP2) helices and turns with a core filled with H-bonds and no hydrophobic groups (Fig. 1).The H-bond network between the PP2 helices (6), PP2 1-6 , requires close packing, which would be precluded by the presence of a C β atom. Thus, the PP2 helices are defined by glycine (Gly) repeats (GXX or GGX, where X is any other amino acid), which enable the hydrogen-bond network. As a consequence, the sfAFP molecule has a low-complexity glycine-rich sequence [37/81 Gly residues, or 46%; typical is 6, or 7% (7)]. The sfAFP core is well packed with essentially no interior void volumes, even when probed using a 0.5-Å radius sphere (8). sfAFP also contains two disulfide bonds, C1-C28 and C13-C43.Notably, no side chains are buried in sfAFP's core (2). All 12 hydrophobic side chains (V 4 , K 2 , and P 6 ) are surface exposed. Upon folding, sfAFP buries about 20 Å 2 ·res −1 of hydrophobic surface area compared with an average of 50 Å 2 ·res −1 for a set of 34 proteins of similar size (Fig. 2A). The difference equates to a decrease in stability of ∼1 or 1.4 kcal·mol −1 ·res −1 , assuming a surface tension coefficient of γ ∼ 34 or 47 cal·mol −1 ·Å −2 based on classical (9) or Flory-Huggins theory (10), respectively. Even the lower bound of 1 kcal·mol −1 ·res −1 represents a significant stability loss, and it is not obvious which energetic terms could compensate for the reduction in hydrophobic burial.Because hydrophobic burial is generally regarded as the basis of protein stability a...

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Local Order in the Unfolded State: Conformational Biases and Nearest Neighbor Interactions

Cited by 57 publications

References 195 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

Rigidity and flexibility in the tetrasaccharide linker of proteoglycans from atomic‐resolution molecular simulation

Perplexing cooperative folding and stability of a low-sequence complexity, polyproline 2 protein lacking a hydrophobic core

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