Energy landscapes of Aβ monomers are sculpted in accordance with Ostwald’s rule of stages

Author:

Chakraborty DebayanORCID,Straub John E.ORCID,Thirumalai DORCID

Abstract

AbstractThe transition from a disordered to an assembly-competent and sparsely populated monomeric state (N*) in amyloidogenic sequences is a crucial event in the aggregation cascade. Using a well-calibrated model for Intrinsically Disordered Proteins (IDPs), we show that the N* states, which bear considerable resemblance to distinct polymorphic fibril structures found in experiments, not only appear as excitations on the monomer free energy landscapes of Aβ40 and Aβ42 but also initiate the aggregation cascade. Interestingly, for Aβ42, the transitions to the different N* states are in accord with Ostwald’s rule of stages, with the least stable structures forming ahead of thermodynamically favored structures, which appear only on longer time-scales. Despite having similar topographies, the Aβ40 and Aβ42 monomer landscapes exhibit different extent of ruggedness, particularly in the vicinity of N* states, which we show have profound implications in dictating the intramolecular diffusion rates, and subsequent self-assembly into higher order structures. The network of connected kinetic states, which for Aβ42 is considerably more complex than for Aβ40, shows that the most favored dimerization routes proceed via the N* states. Direct transition between the disordered ground states within the monomer and dimer basins is less likely. The Ostwald’s rule of stages holds widely, qualitatively explaining the unusual features in other fibril forming IDPs, such as Fused in Sarcoma (FUS). Similarly, the N* theory accounts for dimer formation in small disordered polyglutamine peptides, implicated in the Huntington disease.Graphical TOC Entry

Publisher

Cold Spring Harbor Laboratory

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