Quantum mechanical studies on model α‐pleated sheets

Wu, Hao; Canfield, Alana; Adhikari, Jhashanath; Huo, Shuanghong

doi:10.1002/jcc.21408

Cited by 10 publications

(9 citation statements)

References 40 publications

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“…The directionality of growth is rationalized by a key feature of the linear colloidal aggregation model: the appearance of an asymmetric charge distribution leading to a finite dipole moment in the colloidal spheroids. A possible mechanism for generating the required dipole-dipole asymmetry (29) is the formation of a-sheet secondary structure, proposed by numerous investigators (29,(36)(37)(38)(39) as a transient phase in protein amyloidosis. In the a-sheet configuration, all of the NH groups are on one side and all of the carbonyl groups are on the other side of the polypeptide strand.…”

Section: Discussionmentioning

confidence: 99%

Supramolecular Non-Amyloid Intermediates in the Early Stages of α-Synuclein Aggregation

Fauerbach

Yushchenko

Shahmoradian

et al. 2012

Biophysical Journal

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The aggregation of α-synuclein is associated with progression of Parkinson's disease. We have identified submicrometer supramolecular structures that mediate the early stages of the overall mechanism. The sequence of structural transformations between metastable intermediates were captured and characterized by atomic force microscopy guided by a fluorescent probe sensitive to preamyloid species. A novel ~0.3-0.6 μm molecular assembly, denoted the acuna, nucleates, expands, and liberates fibers with distinctive segmentation and a filamentous fuzzy fringe. These fuzzy fibers serve as precursors of mature amyloid fibrils. Cryo-electron tomography resolved the acuna inner structure as a scaffold of highly condensed colloidal masses interlinked by thin beaded threads, which were perceived as fuzziness by atomic force microscopy. On the basis of the combined data, we propose a sequential mechanism comprising molecular, colloidal, and fibrillar stages linked by reactions with disparate temperature dependencies and distinct supramolecular forms. We anticipate novel diagnostic and therapeutic approaches to Parkinson's and related neurodegenerative diseases based on these new insights into the aggregation mechanism of α-synuclein and intermediates, some of which may act to cause and/or reinforce neurotoxicity.

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Section: Discussionmentioning

confidence: 99%

Supramolecular Non-Amyloid Intermediates in the Early Stages of α-Synuclein Aggregation

Fauerbach

Yushchenko

Shahmoradian

et al. 2012

Biophysical Journal

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“…There is also indirect experimental evidence12–14 that supports this. However, density functional calculations on a two‐stranded acetyl‐(Ala) 2 ‐ N ‐methylamine model showed that the α‐sheet conformation had a 13.6 kcal/mol higher free energy than the corresponding β‐sheet conformation,15 although recent MD simulations on a polyglutamine α‐sheet suggest a rather stable structure 16. Given that there exists plenty of experimental evidence to suggest the mature fibril has a β structure,2, 3 any α‐sheet intermediate would convert to β‐sheet via peptide plane flips during formation of the fibril.…”

Section: Introductionmentioning

confidence: 98%

Simulation of the β‐ to α‐sheet transition results in a twisted sheet for antiparallel and an α‐nanotube for parallel strands: Implications for amyloid formation

Hayward

Milner‐White

2011

Proteins

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α-sheet has been proposed to be the main constituent of the toxic amyloid intermediate. Molecular dynamics simulations on proteins known to be involved in amyloid diseases have demonstrated that β-sheet can, under certain conditions, spontaneously convert to α-sheet via ββ→α(R)α(L) peptide-plane flipping. Using torsion-angle driving to simulate this flip the transition has been investigated for parallel and antiparallel sheets. Concerted and sequential flipping processes were simulated, the former allowing direct calculation of helical parameters. For antiparallel sheet, the strands tend to splay apart during the transition. This can be understood by consideration of the geometry of repeating dipeptide conformations. At the end of the transition antiparallel α-sheet is slightly twisted, comprising gently curving strands. In parallel sheet, the strands maintain identical conformations and stay hydrogen bonded during the transition as they curl up to suggest a hitherto unseen structure, the multi-helix α-nanotube. Intriguingly, the α-nanotube has some of the characteristics of the parallel β-helix, a single-helix structure also implicated in amyloid. Unlike the β-helix, α-nanotube formation could involve identical strands aligning with each other in register as in most amyloids.

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“…While not yet seen in nature, simulations indicate that α-pleated sheets can form as kinetic intermediates in unfolding processes [15][16][17][18]. More generally, a broad range of protein structures could in principle be built from polypeptide motifs possessing two rota-tional states [19,20].…”

Section: Introductionmentioning

confidence: 99%

The Ramachandran Number: An Order Parameter for Protein Geometry

2016

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Three-dimensional protein structures usually contain regions of local order, called secondary structure, such as α-helices and β-sheets. Secondary structure is characterized by the local rotational state of the protein backbone, quantified by two dihedral angles called ϕ and ψ. Particular types of secondary structure can generally be described by a single (diffuse) location on a two-dimensional plot drawn in the space of the angles ϕ and ψ, called a Ramachandran plot. By contrast, a recently-discovered nanomaterial made from peptoids, structural isomers of peptides, displays a secondary-structure motif corresponding to two regions on the Ramachandran plot [Mannige et al., Nature 526, 415 (2015)]. In order to describe such ‘higher-order’ secondary structure in a compact way we introduce here a means of describing regions on the Ramachandran plot in terms of a single Ramachandran number, , which is a structurally meaningful combination of ϕ and ψ. We show that the potential applications of are numerous: it can be used to describe the geometric content of protein structures, and can be used to draw diagrams that reveal, at a glance, the frequency of occurrence of regular secondary structures and disordered regions in large protein datasets. We propose that might be used as an order parameter for protein geometry for a wide range of applications.

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Quantum mechanical studies on model α‐pleated sheets

Cited by 10 publications

References 40 publications

Supramolecular Non-Amyloid Intermediates in the Early Stages of α-Synuclein Aggregation

Supramolecular Non-Amyloid Intermediates in the Early Stages of α-Synuclein Aggregation

Simulation of the β‐ to α‐sheet transition results in a twisted sheet for antiparallel and an α‐nanotube for parallel strands: Implications for amyloid formation

The Ramachandran Number: An Order Parameter for Protein Geometry

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