A <scp>DFT</scp> study of structure and stability of pleated and rippled cross‐β sheets with hydrophobic sidechains

Raskatov, Jevgenij A.

doi:10.1002/bip.23391

Cited by 12 publications

(29 citation statements)

References 35 publications

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“…However, we note that folding possibilities for heterochiral peptides LD1 – LD4 are not limited to the hairpin conformations implied by the drawings; larger turn segments are possible. An alternative explanation for the distinction between homochiral and heterochiral peptide isomers documented here is that the rippled β‐sheet mode of antiparallel strand association is intrinsically less favorable than the pleated β‐sheet mode of antiparallel strand association in aqueous solution, at least for two strands [30] . This hypothesis is consistent with conclusions drawn by Chung and Nowick for H‐bonded‐driven strand associations in a nonpolar solvent [16] .…”

Section: Figuresupporting

confidence: 90%

Comparisons of β‐Hairpin Propensity Among Peptides with Homochiral or Heterochiral Strands

Liu

Gellman

2021

ChemBioChem

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Assemblies of racemic β‐sheet‐forming peptides have attracted attention for biomedical applications because racemic forms of peptides can self‐associate more avidly than do single enantiomers. In 1953, Pauling and Corey proposed “rippled β‐sheet” modes of H‐bond‐mediated interstrand assembly for alternating L‐ and D‐peptide strands; this structural hypothesis was complementary to their proposal of “pleated β‐sheet” assembly for L‐peptides. Although no high‐resolution structure has been reported for a rippled β‐sheet, there is strong evidence for the occurrence of rippled β‐sheets in some racemic peptide assemblies. Here we compare propensities of peptide diastereomers in aqueous solution to form a minimum increment of β‐sheet in which two antiparallel strands associate. β‐Hairpin folding is observed for homochiral peptides with aligned nonpolar side chains, but no β‐hairpin population can be detected for diastereomers in which one strand contains L residues and the other contains D residues. These observations suggest that rippled β‐sheet assemblies are stabilized by interactions between β‐sheet layers rather than interactions within these layers.

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Section: Figuresupporting

confidence: 90%

Comparisons of β‐Hairpin Propensity Among Peptides with Homochiral or Heterochiral Strands

Liu

Gellman

2021

ChemBioChem

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“…Energetics may be different for more extended sheets. 67 DFT calculations conducted thus far only model the isolated LVFFA fragment, not taking into account that there are other segments within Aβ that may also form rippled interfaces, which may bias the system toward the parallel rippled sheet or other structures. Future experimental work may provide more conclusive structural information on Aβ-CI fibrils.…”

Section: Recent Advancesmentioning

confidence: 99%

“… 68 The antiparallel structures were built from Pauling-Corey coordinates, and all four structures were N-terminally acetylated and C-terminally amidated, and fully geometry-optimized as described previously. 63 , 66 , 67 , 69 …”

Section: Recent Advancesmentioning

confidence: 99%

Defining the Landscape of the Pauling-Corey Rippled Sheet: An Orphaned Motif Finding New Homes

Raskatov

Nilsson

2021

Acc. Chem. Res.

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Conspectus When peptides are mixed with their mirror images in an equimolar ratio, two-dimensional periodic structural folds can form, in which extended peptide strands are arrayed with alternating chirality. The resultant topography class, termed the rippled β-sheet, was introduced as a theoretical concept by Pauling and Corey in 1953. Unlike other fundamental protein structural motifs identified around that time, including the α-helix and the pleated β-sheet, it took several decades before conclusive experimental data supporting the proposed rippled β-sheet motif were gained. Much of the key experimental evidence was provided over the course of the past decade through the concurrent efforts of our three laboratories. Studies that focused on developing new self-assembling hydrogel materials have shown that certain amphiphilic peptides form fibrils and hydrogel networks that are more rigid and have a higher thermodynamic stability when made from racemic peptide mixtures as opposed to pure enantiomers. Related interrogation of assemblies composed of mixtures of l - and d -amphiphilic peptides confirmed that the resulting fibrils were composed of alternating l / d peptides consistent with rippled β-sheets. It was also demonstrated that mirror-image amyloid beta (Aβ) could act as a molecular chaperone to promote oligomer-to-fibril conversion of the natural Aβ enantiomer, which was found to reduce Aβ neurotoxicity against different neuronal cell models. With a cross-disciplinary approach that combines experiment and theory, our three laboratories have demonstrated the unique biophysical, biochemical, and biological properties that arise upon mixing of peptide enantiomers, in consequence of rippled β-sheet formation. In this Account, we give an overview of the early history of the rippled β-sheet and provide a detailed structural description/definition of this motif relative to the pleated β-sheet. We then summarize the key findings, obtained on three unique sets of aggregating mirror-image peptide pairs through independent efforts of our three laboratories, and use these results to delineate the landscape of the rippled β-sheet structural motif to inspire future studies. Peptide sequence parameters that favor rippled β-sheet assembly are described, along with the accompanying kinetic and thermodynamic properties, as well as the resulting emergent physical properties of the assemblies. The Account then concludes with a brief overview of some key unresolved challenges in this nascent field. There is much potential for future applications of this unique supramolecular motif in the realm of materials design and biomedical research. We hope this Account will stimulate much-needed discussion of this fascinating structural class to eventually produce a fully quantitative, rational framework for the molecular engineering of rippled β-sheets in the future.

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“…These observations are in agreement with reported density functional theory simulations, explaining that the formation of racemic rippled β-sheet fibrils is energetically more favorable than that of enantiomerically pure pleated ones. 35 , 36 Moreover, the recently accelerated fibrillation process upon mixing of mirror-image peptides was reported. 37 This also explains why spontaneous resolution from the D/L mixture into enantiopure amyloid fibrils is unfavorable.…”

Section: Results and Discussionmentioning

confidence: 99%

Autofluorescence of Amyloids Determined by Enantiomeric Composition of Peptides

et al. 2021

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Amyloid fibrils are peptide or protein aggregates possessing a cross-β-sheet structure. They possess intrinsic fluorescence property, which is still not fully understood. Herein, we compare structural and optical properties of fibrils formed from L- and D-enantiomers of the (105–115) fragment of transthyretin (TTR) and from their racemic mixture. Our results show that autofluorescence of fibrils obtained from enantiomers differs from that of fibrils from the racemic mixture. In order to elucidate the origin of observed differences, we analyzed the structure and morphology of fibrils and showed how variations in β-sheet organization influence optical properties of fibrils. We clarified the contribution of aromatic rings and the amyloid backbone to the final blue-green emission of fibrils. This work demonstrates how enantiomeric composition of amino acids allows us to modulate the self-assembly and final morphology of well-defined fibrillar bionanostructures with optical properties controlled by supramolecular organization.

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A DFT study of structure and stability of pleated and rippled cross‐β sheets with hydrophobic sidechains

Cited by 12 publications

References 35 publications

Comparisons of β‐Hairpin Propensity Among Peptides with Homochiral or Heterochiral Strands

Comparisons of β‐Hairpin Propensity Among Peptides with Homochiral or Heterochiral Strands

Defining the Landscape of the Pauling-Corey Rippled Sheet: An Orphaned Motif Finding New Homes

Autofluorescence of Amyloids Determined by Enantiomeric Composition of Peptides

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