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首页> 外文期刊>Biotechnology Progress >Osmolyte Controlled Fibrillation Kinetics of Insulin: New Insight into Fibrillation Using the Preferential Exclusion Principle
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Osmolyte Controlled Fibrillation Kinetics of Insulin: New Insight into Fibrillation Using the Preferential Exclusion Principle

机译：胰岛素的渗透液控制的原纤化动力学：使用优先排除原理对原纤化的新见解

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Amyloid proteins are converted from their native-fold to long ^-sheet-rich fibrils in a typical sigmoidal time-dependent protein aggregation curve. This reaction process from monomer or dimer to oligomer to nuclei and then to fibrils is the subject of intense study. The main results of this work are based on the use of a well-studied model amyloid protein, insulin, which has been used in vitro by others. Nine osmolyte molecules, added during the protein aggregation process for the production of amyloid fibrils, slow-down or speed up the process depending on the molecular structure of each osmolyte. Of these, all stabilizing osmolytes (sugars) slow down the aggregation process in the following order: tri > di > monosaccharides, whereas destabilizing osmolytes (urea, guanidium hydrochloride) speed up the aggregation process in a predictable way that fits the trend of all osmolytes. With respect to kinetics, we illustrate, by adapting our earlier reaction model to the insulin system, that the intermediates (trimers, tetramers, pentamers, etc.) are at very low concentrations and that nucleation is orders of magnitude slower than fibril growth. The results are then collated into a cogent explanation using the preferential exclusion and accumulation of osmolytes away from and at the protein surface during nucleation, respectively. Both the heat of solution and the neutral molecular surface area of the osmolytes correlate linearly with two fitting parameters of the kinetic rate model, that is, the lag time and the nucleation rate prior to fibril formation. These kinetic and thermodynamic results support the preferential exclusion model and the existence of oligomers including nuclei and larger structures that could induce toxicity.
机译：在典型的S形时间依赖性蛋白聚集曲线中，淀粉样蛋白从其天然折叠转变为长的富含β片的原纤维。从单体或二聚体到低聚物再到核再到原纤维的这一反应过程是深入研究的主题。这项工作的主要结果是基于使用经过充分研究的模型淀粉样蛋白，胰岛素的模型，该模型已被其他人体外使用。根据蛋白质渗透过程的分子结构，在蛋白质聚集过程中添加的九种渗透电解质分子可减慢或加快该过程，以产生淀粉样蛋白原纤维。其中，所有稳定的渗透物（糖）按以下顺序减慢聚集过程：tri> di>单糖，而不稳定的渗透物（尿素，盐酸胍）以可预测的方式加快聚集过程，从而适应所有渗透物的趋势。 。关于动力学，我们通过使我们较早的反应模型适应胰岛素系统来说明，中间体（三聚体，四聚体，五聚体等）的浓度非常低，成核比原纤维的生长慢几个数量级。然后，通过分别在成核过程中优先排除和积累远离蛋白质表面和在蛋白质表面的渗透物，将结果整理为有力的解释。溶液热和渗透压的中性分子表面积均与动力学速率模型的两个拟合参数线性相关，即滞后时间和原纤维形成之前的成核速率。这些动力学和热力学结果支持优先排除模型，并支持包括核和可能诱发毒性的较大结构在内的低聚物。

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