Propensity to form amyloid fibrils is encoded as excitations in the free energy landscape of monomeric proteins.
Propensity to form amyloid fibrils is encoded as excitations in the free energy landscape of monomeric proteins.
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DOI：
10.1016/j.jmb.2014.05.007
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发表时间：
2014-07-15
影响因子：
5.6
通讯作者：
Thirumalai D
中科院分区：
文献类型：
--
作者：
Zhuravlev PI;Reddy G;Straub JE;Thirumalai D
当单体进入准备形成淀粉样原纤维的异常构象时，就会引发与许多疾病相关的蛋白质聚集。我们通过对 src SH3 域的模拟表明，机械力增强了易于聚集 (N*) 状态的数量，这些状态在无力原生条件下很少出现，但被编码在原生波动频谱中。 SH3 的折叠相图作为变性剂浓度 ([C])、机械力 (f) 和温度的函数，表现出明显的两态行为，但没有揭示难以捉摸的 N* 态的存在。有趣的是，在所有 [C] 和 f 处分隔折叠和展开状态的相边界落在主曲线上，可以使用磁场中的超导体进行类比来定量描述。自由能分布作为分子延伸 (R) 的函数，可在拉伸实验 (R) 中获得，揭示了类似天然的 N* 的存在，以及无序的溶剂暴露的氨基末端 β 链。 N*态的结构与通过NMR分散实验在Fyn SH3中发现的结构相同。我们表明，原纤维形成的时间尺度可以根据 N* 态的总体来估计，这是由天然结构和 N* 态之间的自由能隙决定的，这一发现可用于评估蛋白质的原纤维形成倾向。 N* 态的结构用于表明寡聚体的形成和可能的原纤维路径是通过 SH3 结构域中的结构域交换机制发生的。
Protein aggregation, linked to many of diseases, is initiated when monomers access rogue conformations that are poised to form amyloid fibrils. We show, using simulations of src SH3 domain, that mechanical force enhances the population of the aggregation prone (N*) states, which are rarely populated under force free native conditions, but are encoded in the spectrum of native fluctuations. The folding phase diagrams of SH3 as a function of denaturant concentration ([C]), mechanical force (f), and temperature exhibit an apparent two-state behavior, without revealing the presence of the elusive N* states. Interestingly, the phase boundaries separating the folded and unfolded states at all [C] and f fall on a master curve, which can can be quantitatively described using an analogy to superconductors in a magnetic field. The free energy profiles as a function of the molecular extension (R), which are accessible in pulling experiments, (R), reveal the presence of a native-like N* with a disordered solvent-exposed amino terminal β-strand. The structure of the N* state is identical to that found in Fyn SH3 by NMR dispersion experiments. We show that the time scale for fibril formation can be estimated from the population of the N* state, determined by the free energy gap separating the native structure and the N* state, a finding that can be used to assess fibril forming tendencies of proteins. The structures of the N* state are used to show that oligomer formation and likely route to fibrils occur by a domain-swap mechanism in SH3 domain.