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

Abstract

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.

The polyglutamine amyloid nucleus in living cells is a monomer with competing dimensions of order

“…We did find, however, that once an incipient Q zipper formed, phase separation strongly promoted its maturation to amyloid. This is consistent with lamination producing a multi-subunit templating surface; with the fact that increasing concentrations stabilize short beta strand interactions (T. M. Phan and Schmit, 2020); and with observations that polyQ amyloid elongation can occur without full consolidation to the fibril structure (Walters et al, 2012). To the extent that amyloid-associated soluble polyQ species drive disease, condensation would be more likely to ameliorate than exacerbate proteotoxicity.…”