科研之友
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摘要
Amyloid-beta (A beta) oligomers appear to play a pivotal role in Alzheimer's disease. A 42 residue long alloform, A beta 42, is closely related to etiology of the disease. In vitro results show evidences of hexamers; however structures of these hexamers have not been resolved experimentally. Here, we use discrete molecular dynamics (DMD) to analyze long duration stabilities of A beta 42 hexamer models developed previously in our lab. The hydrophobic core of these models is a six-stranded beta-barrel with 3-fold radial symmetry formed by residues 30-40. This core is shielded from water by residues 1-28. The nine models we analyzed differ by the relative positions of the core beta-strands, and whether the other segments surrounding the core contain a helices or beta-strands. A model of an annular protofibril composed of 36 A beta peptides was also simulated. Results of these model simulations were compared with results of aggregation simulations that started from six well separated random coils of A beta 42 and with simulations of two known beta-barrel structures. These results can be categorized into three groups: stable models with properties similar or superior to those of experimentally determined beta-barrel proteins, aggregation-prone models, and an amorphous aggregate from random coils. Conformations at the end of the simulation for aggregation-prone models have exposed hydrophobic core with dangling beta-strands on the surface. Hydrogen bond patterns within the beta-barrel were a critical factor for stability of the beta-barrel models. Aggregation-prone conformations imply that the association of these hexamers may be possible, which could lead to the formation of larger assemblies.
- 出版日期2011-2
