PDF(Pubmed)
Abstract：
Amphiphilic peptides, such as Aß amyloids, can adsorb at an interface between two immiscible electrolyte solutions (ITIES). Based on previous work (vide infra), a hydrophilic/hydrophobic interface is used as a simple biomimetic system for studying drug interactions. The ITIES provides a 2D interface to study ion-transfer processes associated with aggregation, as a function of Galvani potential difference. Here, the aggregation/complexation behaviour of Aβ(1-42) is studied in the presence of Cu (II) ions, together with the effect of a multifunctional peptidomimetic inhibitor (P6). Cyclic and differential pulse voltammetry proved to be particularly sensitive to the detection of the complexation and aggregation of Aβ(1-42), enabling estimations of changes in lipophilicity upon binding to Cu (II) and P6. At a 1:1 ratio of Cu (II):Aβ(1-42), fresh samples showed a single DPV (Differential Pulse Voltammetry) peak half wave transfer potential (E1/2) at 0.40 V. Upon increasing the ratio of Cu (II) two-fold, fluctuations were observed in the DPVs, indicating aggregation. The approximate stoichiometry and binding properties of Aβ(1-42) during complexation with Cu (II) were determined by performing a differential pulse voltammetry (DPV) standard addition method, which showed two binding regimes. A pKa of 8.1 was estimated, with a Cu:Aβ1-42 ratio~1:1.7. Studies using molecular dynamics simulations of peptides at the ITIES show that Aβ(1-42) strands interact through the formation of β-sheet stabilised structures. In the absence of copper, binding/unbinding is dynamic, and interactions are relatively weak, leading to the observation of parallel and anti-parallel arrangements of β-sheet stabilised aggregates. In the presence of copper ions, strong binding occurs between a copper ion and histidine residues on two peptides. This provides a convenient geometry for inducing favourable interactions between folded β-sheet structures. Circular Dichroism spectroscopy (CD spectroscopy) was used to support the aggregation behaviour of the Aβ(1-42) peptides following the addition of Cu (II) and P6 to the aqueous phase.
摘要：
两亲性肽，如Aβ淀粉样蛋白，可以吸附在两个不混溶的电解质溶液（ITIES）之间的界面。根据以前的工作(见下文)，亲水/疏水界面被用作研究药物相互作用的简单仿生系统。ITIES提供了一个2D接口来研究与聚集相关的离子转移过程，作为伽伐尼电位差的函数。这里,在Cu（II）离子存在下研究了Aβ（1-42）的聚集/络合行为，以及多功能肽模拟物抑制剂(P6)的作用。循环和差分脉冲伏安法被证明对Aβ（1-42）的络合和聚集的检测特别敏感，能够估计与Cu（II）和P6结合后的亲脂性变化。在Cu（II）：Aβ（1-42）的比例为1：1时，新鲜样品在0.40V时显示出单个DPV（差分脉冲伏安法）峰值半波转移电位（E1/2）。在DPV中观察到波动，指示聚合。通过执行差分脉冲伏安法（DPV）标准添加方法，确定了与Cu（II）络合过程中Aβ（1-42）的近似化学计量和结合性质，这显示了两个有约束力的制度。pKa估计为8.1，Cu:Aβ1-42的比例为~1:1.7。在ITIES处使用肽的分子动力学模拟的研究表明,Aβ(1-42)链通过β-折叠稳定结构的形成而相互作用。在没有铜的情况下，绑定/解除绑定是动态的，相互作用相对较弱，导致观察到β-折叠稳定聚集体的平行和反平行排列。在铜离子的存在下，强结合发生在铜离子和两个肽上的组氨酸残基之间。这提供了用于诱导折叠的β-折叠结构之间的有利相互作用的方便的几何结构。在向水相中添加Cu(II)和P6之后,使用圆二色光谱(CD光谱)来支持Aβ(1-42)肽的聚集行为。
