Catalystlike role of impurities in speeding layer-by-layer growth

Phan, Tien M.; Whitelam, Stephen; Schmit, Jeremy D.

doi:10.1103/physreve.100.042114

Cited by 2 publications

(2 citation statements)

References 39 publications

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“…Our coarse-grained representation only accounts for intermolecular backbone H-bonds, however, we can speculate on the effect of molecules associating with the cluster via non- β contacts. Disordered binding will, in general, lower the free energy of pre-nucleation clusters thereby increasing their prevalence (49). If a β -sheet is to nucleate from disordered clusters (11, 12) there will be an entropy cost to orient molecules with the existing growing β -sheet.…”

Section: Discussionmentioning

confidence: 99%

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

Phan

Schmit

2020

Preprint

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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.

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