Graduate Group in Biophysics, University of California, Berkeley, California 94720, United States.
Biochemistry. 2011 Sep 6;50(35):7612-28. doi: 10.1021/bi200732x. Epub 2011 Aug 15.
The interplay of modern molecular simulation and high-quality nuclear magnetic resonance (NMR) experiments has reached a fruitful stage for quantitative characterization of structural ensembles of disordered peptides. Amyloid-β 1-42 (Aβ42), the primary peptide associated with Alzheimer's disease, and fragments such as Aβ21-30 are both classified as intrinsically disordered peptides (IDPs). We use a variety of NMR observables to validate de novo molecular dynamics simulations in explicit water to characterize the tertiary structure ensemble of Aβ42 and Aβ21-30 from the perspective of their classification as IDPs. Unlike the Aβ21-30 fragment that conforms to expectations of an IDP that is primarily extended, we find that Aβ42 samples conformations reflecting all possible secondary structure categories and spans the range of IDP classifications from collapsed structured states to highly extended conformations, making it an IDP with a far more heterogeneous tertiary ensemble.
现代分子模拟与高质量核磁共振（NMR）实验的相互作用已经达到了一个富有成效的阶段，可以对无序肽的结构集合进行定量描述。淀粉样蛋白-β1-42（Aβ42）是与阿尔茨海默病相关的主要肽，而 Aβ21-30 等片段则都被归类为无规卷曲肽（IDP）。我们使用各种 NMR 可观测参数来验证在显式水中进行的从头分子动力学模拟，以从 IDP 分类的角度来描述 Aβ42 和 Aβ21-30 的三级结构集合。与主要伸展的 IDP 相符的 Aβ21-30 片段不同，我们发现 Aβ42 可以采样反映所有可能的二级结构类别的构象，并涵盖 IDP 分类的范围，从塌陷的结构化状态到高度伸展的构象，使其成为具有更异质三级集合的 IDP。
