Comparing the Aggregation Free Energy Landscapes of Amyloid Beta(1-42) and Amyloid Beta(1-40)
WH Zheng and MY Tsai and PG Wolynes, JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 139, 16666-16676 (2017).
Using a predictive coarse-grained protein force field, we compute and compare the free energy landscapes and relative stabilities of amyloid- beta protein (1-42) and amyloid-beta protein (1-40) in their monomeric and oligomeric forms up to the octamer. At the same concentration, the aggregation free energy profile of A beta 42 is more downhill, with a computed solubility that is about 10 times smaller than that of A beta 40. At a concentration of 40 mu M, the clear free energy barrier between the pre-fibrillar tetramer form and the fibrillar pentamer in the A beta 40 aggregation landscape disappears for A beta 42, suggesting that the A beta 42 tetramer has a more diverse structural range. To further compare the landscapes, 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 beta-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 A beta 40 lacks. In general, the two terminal residues strongly stabilize the oligomeric structures for A beta 42 relative to A beta 40, and greatly facilitate the conversion from pre-fibrillar trimers to fibrillar tetramers.
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