Hydrophobic Surface Burial Is the Major Stability Determinant of a Flat, Single-layer β-Sheet

Yan, S. Frank; Gawlak, Grzegorz; Makabe, Koki; Tereshko, Valentina; Koide, Shohei

doi:10.1016/j.jmb.2007.02.003

Cited by 23 publications

(36 citation statements)

References 72 publications

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“…These findings are not entirely unexpected since a hydrophobic origin for β-sheets have been proposed by many researchers now and then [61], [62] and similarly an extremely low polarizability is associated with the origin of α-helices for a long time too [63]. However, such assertions were few and far between in nature and more importantly, did not have a full-fledged general theory to explain the causality behind the observations.…”

Section: Discussionmentioning

confidence: 75%

Revisiting the Myths of Protein Interior: Studying Proteins with Mass-Fractal Hydrophobicity-Fractal and Polarizability-Fractal Dimensions

Banerji

Ghosh

2009

PLoS ONE

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A robust marker to describe mass, hydrophobicity and polarizability distribution holds the key to deciphering structural and folding constraints within proteins. Since each of these distributions is inhomogeneous in nature, the construct should be sensitive in describing the patterns therein. We show, for the first time, that the hydrophobicity and polarizability distributions in protein interior follow fractal scaling. It is found that (barring ‘all-α’) all the major structural classes of proteins have an amount of unused hydrophobicity left in them. This amount of untapped hydrophobicity is observed to be greater in thermophilic proteins, than that in their (structurally aligned) mesophilic counterparts. ‘All-β’(thermophilic, mesophilic alike) proteins are found to have maximum amount of unused hydrophobicity, while ‘all-α’ proteins have been found to have minimum polarizability. A non-trivial dependency is observed between dielectric constant and hydrophobicity distributions within (α+β) and ‘all-α’ proteins, whereas absolutely no dependency is found between them in the ‘all-β’ class. This study proves that proteins are not as optimally packed as they are supposed to be. It is also proved that origin of α-helices are possibly not hydrophobic but electrostatic; whereas β-sheets are predominantly hydrophobic in nature. Significance of this study lies in protein engineering studies; because it quantifies the extent of packing that ensures protein functionality. It shows that myths regarding protein interior organization might obfuscate our knowledge of actual reality. However, if the later is studied with a robust marker of strong mathematical basis, unknown correlations can still be unearthed; which help us to understand the nature of hydrophobicity, causality behind protein folding, and the importance of anisotropic electrostatics in stabilizing a highly complex structure named ‘proteins’.

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Section: Discussionmentioning

confidence: 75%

Revisiting the Myths of Protein Interior: Studying Proteins with Mass-Fractal Hydrophobicity-Fractal and Polarizability-Fractal Dimensions

Banerji

Ghosh

2009

PLoS ONE

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“…The critical importance of nonpolar surface burial in peptide self-assembly has been specifically attributed to single -sheet layer stability and the lateral lamination of -sheet [14], [39], [84], [86], [87].…”

Section: Discussionmentioning

confidence: 99%

Mapping the Conformational Dynamics and Pathways of Spontaneous Steric Zipper Peptide Oligomerization

et al. 2011

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The process of protein misfolding and self-assembly into various, polymorphic aggregates is associated with a number of important neurodegenerative diseases. Only recently, crystal structures of several short peptides have provided detailed structural insights into -sheet rich aggregates, known as amyloid fibrils. Knowledge about early events of the formation and interconversion of small oligomeric states, an inevitable step in the cascade of peptide self-assembly, however, remains still limited. We employ molecular dynamics simulations in explicit solvent to study the spontaneous aggregation process of steric zipper peptide segments from the tau protein and insulin in atomistic detail. Starting from separated chains with random conformations, we find a rapid formation of structurally heterogeneous, -sheet rich oligomers, emerging from multiple bimolecular association steps and diverse assembly pathways. Furthermore, our study provides evidence that aggregate intermediates as small as dimers can be kinetically trapped and thus affect the structural evolution of larger oligomers. Alternative aggregate structures are found for both peptide sequences in the different independent simulations, some of which feature characteristics of the known steric zipper conformation (e.g., -sheet bilayers with a dry interface). The final aggregates interconvert with topologically distinct oligomeric states exclusively via internal rearrangements. The peptide oligomerization was analyzed through the perspective of a minimal oligomer, i.e., the dimer. Thereby all observed multimeric aggregates can be consistently mapped onto a space of reduced dimensionality. This novel method of conformational mapping reveals heterogeneous association and reorganization dynamics that are governed by the characteristics of peptide sequence and oligomer size.

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“…The unfolding curve was interpreted in terms of a three-state model as for the wild-type OspA. 15,26 In this three-state model, the first transition corresponds to unfolding of the C-terminal domain and a portion of the SLB; the second, to that of the rest of the SLB and the N-terminal domain. The overall stability of PSAMIle 5 was nearly identical with that of the wild type (ΔΔG NU 3M = 0.07 kcal/mol), but the first transition was destabilized (ΔΔG NI 3M = − 0.75 kcal/mol) and the second transition was stabilized (ΔΔG IU 3M = 0.82 kcal/mol) (ΔG NU 3M , ΔG NI 3M , and ΔG IU 3M are the free energy difference at 3M urea between the native and unfolded states, that between the native and intermediate states, and that between the intermediate and unfolded states, respectively; ΔΔG NU 3M , ΔΔG NI 3M , and ΔΔG IU 3M are differences in ΔG NU 3M , ΔG NI 3M , and ΔG IU 3M between the wild type and the mutant, respectively).…”

Section: Stable Grafting Of An Oligo-ile Stretch Into the Psammentioning

confidence: 99%

“…2a) significantly perturbs the backbone structure, increasing the C α RMSD to 1.15 Å. 15 Thus, the small structural deviation due to the Ile 5 replacement suggests that the PSAM SLB provides a structural environment that is compatible with a stable conformation of the Ile 5 segment.…”

Section: Stable Grafting Of An Oligo-ile Stretch Into the Psammentioning

confidence: 99%

“…Indeed, the presence of the globular domains would appear to inhibit the lamination of the β-sheet, regardless of its composition. 14,15 The single-layer architecture eliminates complications caused by long-range interactions through a hydrophobic core that are commonly present in a water-soluble β-sheet protein. We have demonstrated that a β-hairpin sequence from the SLB forms β-rich fibrils 16 and that the self-assembly of this β-hairpin segment can be captured within OspA in the form of extended SLB.…”

Section: Introductionmentioning

confidence: 99%

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High-Resolution Structure of a Self-Assembly-Competent Form of a Hydrophobic Peptide Captured in a Soluble β-Sheet Scaffold

Makabe¹,

Biancalana²,

Yan³

et al. 2008

Journal of Molecular Biology

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beta-Rich self-assembly is a major structural class of polypeptides, but still little is known about its atomic structures and biophysical properties. Major impediments for structural and biophysical studies of peptide self-assemblies include their insolubility and heterogeneous composition. We have developed a model system, termed peptide self-assembly mimic (PSAM), based on the single-layer beta-sheet of Borrelia outer surface protein A. PSAM allows for the capture of a defined number of self-assembly-like peptide repeats within a water-soluble protein, making structural and energetic studies possible. In this work, we extend our PSAM approach to a highly hydrophobic peptide sequence. We show that a penta-Ile peptide (Ile(5)), which is insoluble and forms beta-rich self-assemblies in aqueous solution, can be captured within the PSAM scaffold in a form capable of self-assembly. The 1.1-A crystal structure revealed that the Ile(5) stretch forms a highly regular beta-strand within this flat beta-sheet. Self-assembly models built with multiple copies of the crystal structure of the Ile(5) peptide segment showed no steric conflict, indicating that this conformation represents an assembly-competent form. The PSAM retained high conformational stability, suggesting that the flat beta-strand of the Ile(5) stretch primed for self-assembly is a low-energy conformation of the Ile(5) stretch and rationalizing its high propensity for self-assembly. The ability of the PSAM to "solubilize" an otherwise insoluble peptide stretch suggests the potential of the PSAM approach to the characterization of self-assembling peptides.

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Hydrophobic Surface Burial Is the Major Stability Determinant of a Flat, Single-layer β-Sheet

Cited by 23 publications

References 72 publications

Revisiting the Myths of Protein Interior: Studying Proteins with Mass-Fractal Hydrophobicity-Fractal and Polarizability-Fractal Dimensions

Revisiting the Myths of Protein Interior: Studying Proteins with Mass-Fractal Hydrophobicity-Fractal and Polarizability-Fractal Dimensions

Mapping the Conformational Dynamics and Pathways of Spontaneous Steric Zipper Peptide Oligomerization

High-Resolution Structure of a Self-Assembly-Competent Form of a Hydrophobic Peptide Captured in a Soluble β-Sheet Scaffold

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