纳米颗粒大小和形状对淀粉样蛋白生成肽寡聚体形成的影响
Influence of Nanoparticle Size and Shape on Oligomer Formation of an Amyloidogenic Peptide
摘要：
理解大分子拥挤和纳米颗粒对对齐的$β$ -片层（淀粉样蛋白原纤维的主要结构组分）形成的影响是描述\emph{in vivo}蛋白聚集和合成材料与蛋白质之间相互作用的第一步。使用全原子分子模拟在隐式溶剂中，我们说明了纳米颗粒的大小，形状和体积分数的影响，从甲状腺素运载蛋白的淀粉样蛋白生成肽的低聚物形成。令人惊讶的是，我们发现惰性球形拥挤颗粒使由二聚体形成的对齐$β$ -片层不稳定，同时使由三聚体和四聚体组成的$β$ -片层稳定。随着纳米颗粒半径的增加，拥挤效应降低，这意味着较小的拥挤颗粒对最早的淀粉样蛋白种类具有最大的影响。我们解释这些结果使用的理论基础上的耗尽效应。最后，我们发现，球形crowders不稳定有序的$β$ -片二聚体在更大程度上比球形crowders，这强调了纳米颗粒形状对蛋白质聚集的影响。
英文摘要：
Understanding the influence of macromolecular crowding and nanoparticles on the formation of in-register $β$-sheets, the primary structural component of amyloid fibrils, is a first step towards describing \emph{in vivo} protein aggregation and interactions between synthetic materials and proteins. Using all atom molecular simulations in implicit solvent we illustrate the effects of nanoparticle size, shape, and volume fraction on oligomer formation of an amyloidogenic peptide from the transthyretin protein. Surprisingly, we find that inert spherical crowding particles destabilize in-register $β$-sheets formed by dimers while stabilizing $β$-sheets comprised of trimers and tetramers. As the radius of the nanoparticle increases crowding effects decrease, implying smaller crowding particles have the largest influence on the earliest amyloid species. We explain these results using a theory based on the depletion effect. Finally, we show that spherocylindrical crowders destabilize the ordered $β$-sheet dimer to a greater extent than spherical crowders, which underscores the influence of nanoparticle shape on protein aggregation.
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