Theory of Amyloid Fibril Nucleation from Folded Proteins

Zhang, Lingyun; Schmit, Jeremy D.

doi:10.1002/ijch.201600079

Cited by 14 publications

(16 citation statements)

References 55 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This means that amyloid nu- * schmit@phys.ksu.edu cleation is better viewed as a 3D incorporation of amino acid building blocks rather than a 1D or 2D assembly of polypeptide strands. The β-sheet must be 4-6 strands thick to overcome the entropic cost of straightening the first molecule [12], consistent with numerous simulations showing that fibrils shorter than this size are unstable [13][14][15][16][17][18][19][20][21].…”

supporting

confidence: 71%

See 1 more Smart Citation

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

Phan

Schmit

2020

Preprint

Self Cite

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

supporting

confidence: 71%

“…However, the initiation of β-structure from two disordered molecules requires both molecules to lose conformational entropy. As a result, this event is net repulsive [11,12]. This means that amyloid nu- * schmit@phys.ksu.edu cleation is better viewed as a 3D incorporation of amino acid building blocks rather than a 1D or 2D assembly of polypeptide strands.…”

mentioning

confidence: 99%

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

Phan

Schmit

2020

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…The system of three molecules is unstable, so we have developed a stable 3D model. The nucleation rate in 3D model can be written as [ 32 ]

where

and

…”

Section: Discussionmentioning

confidence: 99%

Assembly Mechanism for Aggregation of Amyloid Fibrils

Zhang¹

2018

IJMS

Self Cite

View full text Add to dashboard Cite

The assembly mechanism for aggregation of amyloid fibril is important and fundamental for any quantitative and physical descriptions because it needs to have a deep understanding of both molecular and statistical physics. A theoretical model with three states including coil, helix and sheet is presented to describe the amyloid formation. The corresponding general mathematical expression of N molecule systems are derived, including the partition function and thermodynamic quantities. We study the equilibrium properties of the system in the solution and find that three molecules have the extreme value of free energy. The denaturant effect on molecular assemble is also discussed. Furthermore, we apply the kinetic theories to take account of the nucleation and growth of the amyloid in the solution. It has been shown that our theoretical results can be compared with experimental results.

show abstract

“…Although amyloid nucleation and growth is very complex, classical nucleation theory predicts that the environment of the critical nucleus should influence the structure of the resulting aggregate ( Figure 1a) (36)(37)(38). Nucleation theory is widely applied to direct the crystallization of small molecule polymorphs, and nucleation driven control over amyloid structure has been used to 5 produce fibrils of sufficient purity for X-ray crystallography and solid-state NMR spectroscopy through repeated seeding (17,39).…”

Section: Introductionmentioning

confidence: 99%

Functionalized Mesoporous Silicas Direct Structural Polymorphism of Amyloid-β Fibrils

Lucas

Pan

Verbeke

et al. 2020

Preprint

View full text Add to dashboard Cite

The aggregation of Amyloid-b (Ab) is associated with the onset of Alzheimer's Disease (AD) and involves a complex kinetic pathway as monomers self-assemble into fibrils. A central feature of amyloid fibrils is the existence of multiple structural polymorphs, which complicates the development of disease-relevant structure-function relationships. Developing these relationships requires new methods to control fibril structure. In this work, we demonstrate that mesoporous silicas (SBA-15) functionalized with hydrophobic (SBA-PFDTS) and hydrophilic groups (SBA-PEG) direct the aggregation kinetics and resulting structure of Ab1-40 fibrils. The hydrophilic SBA-PEG had little effect on amyloid kinetics while as-synthesized and hydrophobic SBA-PFDTS accelerated aggregation kinetics. Subsequently, we quantified the relative population of fibril structures formed in the presence of each material using electron microscopy. Fibrils formed from Ab1-40 exposed to SBA-PEG were structurally similar to control fibrils. In contrast, Ab1-40 incubated with SBA-15 or SBA-PFDTS formed fibrils with shorter cross-over distances that were more structurally representative of fibrils found in AD patient-derived samples. Overall, these results suggest that mesoporous silicas and other exogenous materials are promising scaffolds for the de novo production of specific fibril polymorphs of Ab1-40 and other amyloidogenic proteins. Significance StatementA major challenge in understanding the progression of Alzheimer's Disease lies in the various fibril structures, or polymorphs, adopted by Amyloid-b (Ab). Heterogenous fibril populations may be responsible for different disease phenotypes and growing evidence suggests that Ab fibrils formed in vitro are structurally distinct from patient-derived fibrils. To help bridge 3 this gap, we used surface-functionalized mesoporous silicas to influence the formation of Ab1-40 fibrils and evaluated the distribution of resulting fibril polymorphs using electron microscopy (EM). We found that silicas modified with hydrophobic surfaces resulted in fibril populations with shorter cross-over distances that are more representative of Ab fibrils observed ex vivo. Overall, our results indicate that mesoporous silicas may be leveraged for the production of specific Ab polymorphs.

show abstract

Theory of Amyloid Fibril Nucleation from Folded Proteins

Cited by 14 publications

References 55 publications

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

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

Assembly Mechanism for Aggregation of Amyloid Fibrils

Functionalized Mesoporous Silicas Direct Structural Polymorphism of Amyloid-β Fibrils

Contact Info

Product

Resources

About