TY - JOUR T1 - Conformational entropy limits the transition from nucleation to elongation in amyloid aggregation JF - bioRxiv DO - 10.1101/2020.06.22.165423 SP - 2020.06.22.165423 AU - Tien M. Phan AU - Jeremy D. Schmit Y1 - 2020/01/01 UR - http://biorxiv.org/content/early/2020/06/23/2020.06.22.165423.abstract N2 - 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.Competing Interest StatementThe authors have declared no competing interest. ER -