Contribution of Electrostatics in the Fibril Stability of a Model Ionic-Complementary Peptide
Contribution of Electrostatics in the Fibril Stability of a Model Ionic-Complementary Peptide
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DOI：
10.1021/acs.biomac.5b01092
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发表时间：
2015-12-01
影响因子：
6.2
通讯作者：
Arosio, Paolo
中科院分区：
文献类型：
--
作者：
Owczarz, Marta;Casalini, Tommaso;Arosio, Paolo
在这项工作中，我们通过尺寸排阻色谱和分子模拟相结合，量化了静电相互作用在模型两亲性肽 (RADA 164) 自组装成纤维结构中的作用。对于所研究的肽，发现+0.75的净电荷代表促进规则淀粉样原纤维形成的理想条件。较低的净电荷有利于无定形沉淀物的形成，而较大的净电荷使原纤维聚集体不稳定并促进单体从原纤维末端可逆解离。通过量化这种可逆反应的平衡常数对 pH 值和肽净电荷的依赖性，我们表明静电相互作用很大程度上有助于原纤维形成的自由能。添加中等浓度 (0.3-1 M) 的盐和带电去稳定剂（盐酸胍）可使单体-原纤维平衡向原纤维状态移动。虽然第一个效应只能通过静电排斥的电荷屏蔽来解释，但在盐酸胍存在下促进原纤维形成也归因于肽构象的修饰。这项工作的结果表明，尽管肽构象和表面电荷分布也有助于聚集倾向，但整体肽净电荷是与原纤维稳定性密切相关的关键特性。
In this work we quantified the role of electrostatic interactions in the self-assembly of a model amphiphilic peptide (RADA 164) into fibrilar structures by a combination of size exclusion chromatography and molecular simulations. For the peptide under investigation, it is found that a net charge of +0.75 represents the ideal condition to promote the formation of regular amyloid fibrils. Lower net charges favor the formation of amorphous precipitates, while larger net charges destabilize the fibrillar aggregates and promote a reversible dissociation of monomers from the ends of the fibrils. By quantifying the dependence of the equilibrium constant of this reversible reaction on the pH value and the peptide net charge, we show that electrostatic interactions contribute largely to the free energy of fibril formation. The addition of both salt and a charged destabilizer (guanidinium hydrochloride) at moderate concentration (0.3-1 M) shifts the monomer-fibril equilibrium toward the fibrillar state. Whereas the first effect can be explained by charge screening of electrostatic repulsion only, the promotion of fibril formation in the presence of guanidinium hydrochloride is also attributed to modifications of the peptide conformation. The results of this work indicate that the global peptide net charge is a key property that correlates well with the fibril stability, although the peptide conformation and the surface charge distribution also contribute to the aggregation propensity.