Molecular dynamics analysis of the aggregation propensity of polyglutamine segments

Wen, Jingran; Scoles, Daniel R.; Facelli, Julio C.

doi:10.1371/journal.pone.0178333

Cited by 25 publications

(13 citation statements)

References 52 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, this ensemble did not match well with the experimental result, probably due to the force field that caused this mismatch. So we did another 4 conventional MD simulations using AMBER ff99SB force field 62,63 and 500-ns duration for each simulation. Different approaches have been proposed for deriving representative ensembles such as ENSEMBLE that assigns weights to the different conformations of the pool 35,36 , and ASTEROIDS that relies on a genetic algorithm to select sub-ensembles 37,38 .…”

Section: Methodsmentioning

confidence: 99%

Structural and dynamic studies reveal that the Ala-rich region of ataxin-7 initiates α-helix formation of the polyQ tract but suppresses its aggregation

Hong

Wang

Xue

et al. 2019

Sci Rep

View full text Add to dashboard Cite

Ataxin-7 (Atx7) is a disease-related protein associated with the pathogenesis of spinocerebellar ataxia 7, while its polyglutamine (polyQ) tract in N-terminus is the causative source of aggregation and proteinopathy. We investigated the structure, dynamics and aggregation properties of the N-terminal 62-residue fragment of Atx7 (Atx7-N) by biochemical and biophysical approaches. The results showed that the normal Atx7-N with a tract of 10 glutamines (10Q) overall adopts a flexible and disordered structure, but it may contain a short or small population of helical structure in solution. PolyQ expansion increases the α-helical propensity of the polyQ tract and consequently enhances its transformation into β-sheet structures during amyloid aggregation. An alanine-rich region (ARR) just ahead of the polyQ tract forms a local and relatively stable α-helix. The ARR α-helix can initiate and stabilize helical formation of the following polyQ tract, but it may suppress aggregation of the polyQ-expanded Atx7-N both in vitro and in cell. Thus, the preceding ARR segment in Atx7-N may influence the dynamic structure and aggregation property of the polyQ tract and even determine the threshold of the pathogenic polyQ lengths. This study may gain structural and dynamic insights into amyloid aggregation of Atx7 and help us further understand the Atx7 proteinopathy based on polyQ expansion.

show abstract

Section: Methodsmentioning

confidence: 99%

Structural and dynamic studies reveal that the Ala-rich region of ataxin-7 initiates α-helix formation of the polyQ tract but suppresses its aggregation

Hong

Wang

Xue

et al. 2019

Sci Rep

View full text Add to dashboard Cite

show abstract

“…This additional cost of forming β -sheet structure in the dimer will contribute to the energy barrier that must be surmounted to nucleate a fibril. Despite the fact that each of the three force fields has been favorably evaluated for simulations of polyglutamine (41)(42)(43)(44)(45), they yielded widely different results (Fig. 3d, Table 1).…”

Section: Resultsmentioning

confidence: 99%

Conformational entropy limits the transition from nucleation to elongation in amyloid aggregation

Phan

Schmit

2020

Preprint

View full text Add to dashboard Cite

The formation of amyloid fibrils in Alzheimer's disease and other neurodegenerative disorders is limited by a slow nucleation step due to the entropic cost to initiate the ordered cross-β structure. While the barrier can be lowered if the molecules maintain conformational disorder, poorly ordered clusters provide a poor binding surface for new molecules. To understand these opposing factors, we used all-atom simulations to parameterize a lattice model that treats each amino acid as a binary variable with β-sheet and non-β states. We find that the optimal degree of order in a nucleus depends on protein concentration. Low concentration systems require more ordered nuclei to capture infrequent monomer attachments. The nucleation phase transitions to the elongation phase when the β-sheet core becomes large enough to overcome the initiation cost, at which point further ordering becomes favorable and the nascent fibril efficiently captures new molecules.

show abstract

“…We observed an antiparallel β‐sheet in the four models Q 34 , Q 35 , Q 36 , and Q 40 , whereas in the Q 50 model one parallel and one antiparallel β‐sheet was found. This observation is consistent with the previous study which reveals that the propensity to form β‐sheet content is high when the Q length increases . We also looked into the models with the presence of proline residues and found that these residues did not show much difference in the secondary structure and transformation.…”

Section: Introductionmentioning

confidence: 99%

“…This observation is consistent with the previous study which reveals that the propensity to form β-sheet content is high when the Q length increases. 30 We also looked into the models with the presence of proline residues and found that these residues did not show much difference in the secondary structure and transformation.…”

Section: Introductionmentioning

confidence: 99%

Structural insights into the aggregation mechanism of huntingtin exon 1 protein fragment with different polyQ‐lengths

Priya

Gromiha

2019

J of Cellular Biochemistry

View full text Add to dashboard Cite

Huntington disease is a neurodegenerative disorder caused by the expansion of polyglutamine (polyQ) at the N-terminal of the huntingtin exon 1 protein. The detailed structure and the mechanism behind this aggregation remain unclear and it is assumed that the polyQ undergoes a conformational transition to the β-sheet structure when it aggregates. Investigating the misfolding of polyQ facilitates the determination of the molecular mechanism of aggregation and can potentially help in developing a novel approach to inhibit polyQ aggregation. Moreover, the flanking sequences of the polyQ region play a vital role in structural changes and the aggregation mechanism. We performed all-atom molecular dynamics simulations to gain structural insights into the aggregation mechanism using eight different models with glutamine repeat lengths Q 27 , Q 27 P 11 , Q 34 , Q 35 , Q 36 , Q 40 , Q 50 , and Q 50 P 11 . In the models without flanking polyPs, we noticed that the transformation of a random coil to β-sheet occurs when the number of Q increases. We also found that the flanking polyPs prevent aggregation by decreasing the probability of forming a β-sheet structure. When polyQ length increases, the 17 N-terminal flanking residues are more likely to adopt a β-sheet conformation from α-helix and coil. From our simulations, we suggest that at least 34 glutamines are required for initiating aggregation and 40 residues length is critical for the aggregation of huntingtin exon 1 protein for disease onset. This study provides structural insights into misfolding and the role of flanking sequences in huntingtin aggregation which will further help in developing therapeutic strategies for Huntington's disease.

show abstract

Molecular dynamics analysis of the aggregation propensity of polyglutamine segments

Cited by 25 publications

References 52 publications

Structural and dynamic studies reveal that the Ala-rich region of ataxin-7 initiates α-helix formation of the polyQ tract but suppresses its aggregation

Structural and dynamic studies reveal that the Ala-rich region of ataxin-7 initiates α-helix formation of the polyQ tract but suppresses its aggregation

Conformational entropy limits the transition from nucleation to elongation in amyloid aggregation

Structural insights into the aggregation mechanism of huntingtin exon 1 protein fragment with different polyQ‐lengths

Contact Info

Product

Resources

About