Conformational entropy limits the transition from nucleation to elongation in amyloid aggregation.
Conformational entropy limits the transition from nucleation to elongation in amyloid aggregation.
复制标题
构象熵限制了淀粉样蛋白聚集从成核到伸长的转变。
DOI：
10.1016/j.bpj.2022.06.031
复制
发表时间：
2022
影响因子：
3.4
通讯作者：
Schmit,JeremyD
中科院分区：
文献类型：
--
作者：
Phan,TienM;Schmit,JeremyD
阿尔茨海默病和其他神经退行性疾病中富含β-片层的淀粉样蛋白原纤维的形成受到缓慢成核事件的限制。为了理解无序肽的β折叠的初始形成，我们使用全原子模拟来参数化晶格模型，该模型将每个氨基酸视为具有β折叠和非β折叠状态的二元变量。我们发现，平移和构象熵给新生β-折叠的各向异性的表面张力，可以用来描述与二维经典成核理论的核。由于平移熵依赖于浓度，临界β折叠的纵横比随蛋白质浓度而变化。我们的模型解释了从成核阶段到伸长的转变，即β-折叠核心变得足够大以克服构象熵成本以拉直末端分子的点。此时，细胞核中的β链自发地伸长，这导致更大的结合表面以捕获新分子。这些结果表明，成核对共聚集实验中的序列差异相对不敏感，因为核仅涉及肽的一小部分。
The formation of β-sheet-rich amyloid fibrils in Alzheimer's disease and other neurodegenerative disorders is limited by a slow nucleation event. To understand the initial formation of β-sheets from disordered peptides, we used all-atom simulations to parameterize a lattice model that treats each amino acid as a binary variable with β- and non-β-sheet states. We show that translational and conformational entropy give the nascent β-sheet an anisotropic surface tension that can be used to describe the nucleus with 2D classical nucleation theory. Since translational entropy depends on concentration, the aspect ratio of the critical β-sheet changes with protein concentration. Our model explains the transition from the nucleation phase to elongation as the point where the β-sheet core becomes large enough to overcome the conformational entropy cost to straighten the terminal molecule. At this point the β-strands in the nucleus spontaneously elongate, which results in a larger binding surface to capture new molecules. These results suggest that nucleation is relatively insensitive to sequence differences in coaggregation experiments because the nucleus only involves a small portion of the peptide.