Comparing the Aggregation Free Energy Landscapes of Amyloid Beta(1-42) and Amyloid Beta(1-40).
Comparing the Aggregation Free Energy Landscapes of Amyloid Beta(1-42) and Amyloid Beta(1-40).
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DOI：
10.1021/jacs.7b08089
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发表时间：
2017-11-22
影响因子：
15
通讯作者：
Wolynes PG
中科院分区：
文献类型：
--
作者：
Zheng W;Tsai MY;Wolynes PG
使用预测粗粒度蛋白质力场，我们计算和比较淀粉样β蛋白（1-42）和淀粉样β蛋白（1-40）在单体和寡聚体形式直到八聚体的自由能景观和相对稳定性。在相同浓度下，Aβ42的聚集自由能曲线更向下，计算的溶解度比Aβ40小约10倍。在40 μM的浓度下，Aβ42在Aβ40聚集景观中的前纤维状四聚体形式和纤维状五聚体之间的明显自由能垒消失，表明Aβ42四聚体具有更多样化的结构范围。为了进一步比较的景观，我们开发了一个聚类分析的基础上，配置之间的结构相似性，并使用它来构建一个寡聚化图，捕捉不同的，但结构相似的低聚物的状态之间容易相互转换的路径为两个物种。提出了一种基于β-折叠堆积拓扑结构的低聚物物种分类法。两个寡聚化图谱的比较突出了景观中的几个关键差异，这些差异可归因于Aβ40缺乏的两个额外的C末端残基。一般而言，相对于Aβ40，两个末端残基强烈稳定Aβ42的寡聚体结构，并极大地促进从预纤维状三聚体转化为纤维状四聚体。
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.
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DOI：
10.1126/science.aao2825
发表时间：
2017-10-06
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Gremer L;Schölzel D;Schenk C;Reinartz E;Labahn J;Ravelli RBG;Tusche M;Lopez-Iglesias C;Hoyer W;Heise H;Willbold D;Schröder GF
通讯作者：
Schröder GF
影响因子：
2.9
作者：
Petkova, AT;Yau, WM;Tycko, R
通讯作者：
Tycko, R
DOI：
10.1073/pnas.1218402110
发表时间：
2013-06-11
影响因子：
11.1
作者：
Cohen, Samuel I. A.;Linse, Sara;Knowles, Tuomas P. J.
通讯作者：
Knowles, Tuomas P. J.
影响因子：
8.4
作者：
Cukalevski R;Yang X;Meisl G;Weininger U;Bernfur K;Frohm B;Knowles TPJ;Linse S
通讯作者：
Linse S
影响因子：
4.1
作者：
PLIMPTON, S
通讯作者：
PLIMPTON, S