Comparing the Aggregation Free Energy Landscapes of Amyloid Beta(1–42) and Amyloid Beta(1–40)

Abstract

Using a predictive coarse-grained protein force field, we compute and compare the free energy landscapes and relative stabilities of amyloid-β protein (1-42) and amyloid-β protein (1-40) in their monomeric and oligomeric forms up to the octamer. At the same concentration, the aggregation free energy profile of Aβ42 is more downhill, with a computed solubility that is about ten times smaller than that of Aβ40. At a concentration of 40 μM, the clear free energy barrier between the prefibrillar tetramer form and the fibrillar pentamer in the Aβ40 aggregation landscape disappears for Aβ42, suggesting that the Aβ42 tetramer has a more diverse structural range. To further compare the landcapes, we develop a cluster analysis based on the structural similarity between configurations and use it to construct an oligomerization map that captures the paths of easy interconversion between different but structurally similar states of oligomers for both species. A taxonomy of the oligomer species based on β-sheet stacking topologies is proposed. The comparison of the two oligomerization maps highlights several key differences in the landscapes that can be attributed to the two additional C-terminal residues that Aβ40 lacks. In general, the two terminal residues strongly stabilize the oligomeric structures for Aβ42 relative to Aβ40, and greatly facilitate the conversion from prefibrillar trimers to fibrillar tetramers.

Mitigating Alzheimer’s Disease with Natural Polyphenols: A Review

“…The insoluble A in AD brain tissue is often predominantly [47]. The predicted solubility is 0.4 M for A $% and 0.04 M for A $& [48], which is consistent with the experimental solubility of 0.04 M for A $& [49].…”

“…In both cases, the oligomers are disc-shaped with diameters of 10-15 nm [58]. Using a predictive coarse-grained protein force field, Zheng et al [48] computed and compared the free energy landscapes and relative stabilities of A $& and A $% in their monomeric and oligomeric forms up to the octamer. Several A peptides, linked together through hydrogen bonds, lead to the formation of protofibrils (25-30 Å), comprised of short beta sheets along their width with aligned strands along the lengths.…”

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

“…Recent Aβ42 fibril structures determined using solution-state NMR (44,45), and Cryo-EM (46) seem to corroborate this viewpoint. Previous work based on all-atom studies (29,30,42,47,48) simulations using coarse-grained models (49)(50)(51) further predict that the two isoforms could be associated with different populations of the metastable states, and allude to a sequence-specific conformational heterogeneity that could be a key determinant of the contrasting aggregation propensities.…”

Disorder mediated oligomerization of DISC1 proteins revealed by coarse-grained computer simulations

“…The judicious combination of physical and knowledge based terms has been shown to perform well for de novo predictions of majority of proteins with foldable landscapes including native states and allosteric conformational states of single and multi-domain proteins (25)(26)(27). Thanks to the predictive nature of AWSEM model it has found wide applicability for solving various biophysical problems including predictions of monomeric protein units, protein aggregation (28,29), protein-DNA assembly (30,31), proteins with unstructured regions (32) and recently also for natively disordered proteins (33). In this work we have used the AWSEM Hamiltonian supplemented with electrostatic potential (34) and multiple fragment memories (32,35) to account for disordered nature of the DISC1 sequence.…”