Luminescent Pt(II) tag for monitoring peptide (mis)folding and aggregation processes

今天，非常清楚的是，一种特定材料的功能或性质并不总是来自它的单一成分，还来自分子在空间、时间和能量上的超分子排列，即在溶液中，也在固体中。在某些情况下，分子自发地排列成一个有组织的超分子实体，这种现象被称为自组装。这个过程对生命来说是必不可少的，就像当DNA双链通过配对形成时，当多肽自我组装成蛋白质时，或者当细胞膜由磷脂构建时发生的那样。在所有情况下，分子间相互作用，如氢键、van der Waals相互作用或pi-相互作用都是组装的潜在驱动力。如前所述，肽需要折叠才能实现其功能，然而，对于某些肽，错误折叠和/或自组装可能会发生错误折叠和/或自组装，导致所谓的淀粉样变性，错误折叠的多肽自组装成寡聚b-片状(原纤维)，然后聚集成纤维。最广为人知的淀粉样变会导致阿尔茨海默氏症，但帕金森氏病、II型糖尿病和普恩病毒疾病也属于这类疾病，每种疾病都有不同的蛋白质负责纤维的形成。然而，观察淀粉样多肽在活的介质中的聚集和解聚，需要记者允许实时监测纤维的形成，并区分聚集和非聚集状态。在这方面，铂(II)发光配合物可以作为标记物。由于铂(II)络合物在可见光区发射斯托克斯位移大、量子产率高、激发态寿命长、稳定性高，是理想的生物成像标记材料。这项建议的研究目标是设计一种发光标签来监测淀粉样肽的聚集过程。该项目的创新之处在于，所设计的发光铂(II)标签在聚集后会改变其发射性质。铂(II)络合物将偶联在多肽的N端氨基酸上，并将研究新的[铂]-多肽分子的光物理性质和自组装行为。预计在聚集后，位于多肽末端的铂(II)络合物将相互作用。正如文献报道的那样，堆叠的铂(II)络合物表现出不同的发射光谱，这使得能够识别聚集肽。

Today, it is very clear that the function or properties of a definite material does not always come from its single components, but also from the supramolecular arrangement of the molecules in space, time, and energy, and that is in solution, as well as in the solid state. In some cases, molecules spontaneously arrange in an organized supramolecular entity, the phenomenon being known as self-assembly. This process is essential to life, as it happens when a DNA double-strand forms through pair-matching, when peptides self-assembles into a protein, or when a cell membrane is built by phospholipids. In all cases, intermolecular interactions such as H-bonding, van der Waals interactions, or pi-interactions are the underlying driving force for the assembly.As just mentioned before, a peptide needs to be folded in order to achieve its function, however, for some peptides, misfolding and/or self-assembly can happen and lead to so-called amyloidosis, where misfolded polypeptides self-assemble into oligomeric b-sheets (protofibrils), which then aggregate into fibrils. The most well-known amyloidosis leads to Alzheimer’s disease, but Parkinson’s disease, diabetes type II, and prion diseases also belong to this class of illnesses, in each case a different protein is responsible for the building of the fibrils.However, observing the aggregation and disaggregation of amyloid peptides in living media, would require a reporter allowing monitoring in real time the formation of the fibrils, and differentiating between the aggregated and non-aggregated state. In this respect, Pt(II) luminescent complexes could be used as tag. With their emission in the visible region with a large Stokes shift, their high quantum yields, long excited state lifetimes, and high stability, Pt(II) complexes are ideal to be used as bio-imaging label. The research objective of this proposal is to design a luminescent tag for monitoring the aggregation processes of amyloid-like peptides. The novelty of this project lies in the fact that the designed luminescent Pt(II) tag would change its emission properties upon aggregation. The Pt(II) complex will be coupled on the N-terminal amino-acid of the peptides, and the photophysical properties as well as self-assembly behaviour of the new [Pt]-Peptide molecules will be studied. It is expected that upon aggregation, the Pt(II) complexes located at the end of the peptides will interact. As reported in literature, stacked Pt(II) complexes exhibit a different emission spectrum, which allow then the identification of aggregated peptides.