Differences in the free energies between the excited states of Aβ40 and Aβ42 monomers encode their distinct aggregation propensities

Abstract

of 17Cluster 5Cluster 6 Cluster 8 Cluster 12 Cluster 1+2+3+7 Fig. S8. Clusters 4,5,6,8: Conformational clusters in Aβ40 with conformations with different extents of residual structuring near the N-terminus. Residues 1-10, which are disordered in the fibril structure, are shown in magenta, and residues 11-40, which are ordered in the fibril structure, are shown in light green. These clusters also consist of RC-like structures (see Table S3). The supercluster formed by clusters 1,2,3 and 7 consists of exclusively RC-like structures, and is characterized by a featureless contact map. Clusters in which the conformations with structural signatures of the fibril state are shown in the main text. 13 of 17Cluster 1Cluster 10Cluster 11 Cluster 2+3+8+9 Fig. S9. Different cluster families constituting the Aβ42 monomer ensemble. In cluster 1, the conformations have some structure in the C-terminus. Cluster 10 consists of structures with an ordered N-terminus. In cluster 11, both the termini are disordered. However, some residual structure is present near the middle of the peptide. In these clusters, residues 1-16, which form the disordered region in the fibril structure are shown in magenta, and residues 17-42, which form the ordered region of the fibril, are in green. These clusters also consist of RC-like conformations in addition to those exhibiting different extents of residual structuring. The supercluster formed by clusters 2,3,8 and 9 has a featureless contact map, and consists of exclusively RC-like conformations. The clusters which contain structures that have some resemblance to the monomer units of different Aβ42 polymorphs are shown in the main text.

Thermal Compaction of Disordered and Elastin-like Polypeptides: A Temperature-Dependent, Sequence-Specific Coarse-Grained Simulation Model

“…The charge of an amino acid is assigned to the side-chain bead. Details on the significance these terms, in the context of both folded proteins and disordered sequences, can be found elsewhere 81,82,84,85 .…”

“…First, given that the SOP-IDP model has been shown to capture the chain dimensions under ambient conditions for diverse polypeptide sequences 81,82 , it is not surprising that the temperature-independent model results are already in fair agreement with experiments, with deviations in R h from the experimental values ∼(8-15)%. It is gratifying to observe, that the temperature-dependent parameterization of the model results in improved agreement with experimental values, with maximum deviation now limited to <9%.…”

Amyloid Oligomers: A Joint Experimental/Computational Perspective on Alzheimer’s Disease, Parkinson’s Disease, Type II Diabetes, and Amyotrophic Lateral Sclerosis

“…where c is a constant and P N* is expressed as a percentage. 431 Chakraborty et al 437 τfib of S-bend Aβ42 fibril is around 24 times smaller than Aβ40. 437 This prediction is consistent with recent experiments showing that the rate of Aβ42 fibril formation is about an order of magnitude higher than Aβ40.…”

“…431 Chakraborty et al 437 τfib of S-bend Aβ42 fibril is around 24 times smaller than Aβ40. 437 This prediction is consistent with recent experiments showing that the rate of Aβ42 fibril formation is about an order of magnitude higher than Aβ40. The higher population of N* in Aβ42 than in Aβ40 was also confirmed by all-atom simulations.…”

Different force fields give rise to different amyloid aggregation pathways in molecular dynamics simulations

“…12 In the first part of this study, we elucidate the structural transitions of the three peptide sequences at the monomeric level since it is known that the monomer state has an effect or even controls the aggregation process. [41][42][43][44] Secondly, we investigate the formation of hexamers by these peptides and establish links between the monomer configuration and the oligomer state. To complement this view, we finally check the stability of a preformed steric zipper involving twelve copies of either wt, m1, or m2, providing a conclusive evidence regarding which of the FFs under study is best suited to study amyloid aggregation using MD simulations.…”