Contrasting effects of nanoparticle-protein attraction on amyloid aggregation.
Contrasting effects of nanoparticle-protein attraction on amyloid aggregation.
复制标题
纳米颗粒 - 蛋白吸引对淀粉样蛋白聚集的对比作用。
DOI：
10.1039/c5ra20182a
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发表时间：
2015-01-01
期刊：
影响因子：
3.9
通讯作者：
Ding F
中科院分区：
文献类型：
--
作者：
Radic S;Davis TP;Ke PC;Ding F
实验发现纳米颗粒（NPs）可以促进或抑制蛋白质的淀粉样蛋白聚集，但这种复杂行为的分子机制仍然未知。使用粗粒度的分子动力学模拟，我们研究了不同的强度的非特异性NP-蛋白质的吸引力对淀粉样蛋白聚集的模型蛋白，淀粉样β肽牵连在阿尔茨海默氏病的影响。具体而言，随着NP-肽吸引力的增加，NP表面上的淀粉样蛋白聚集最初是由于表面上的局部蛋白浓度增加和折叠状态的不稳定而促进的。然而，NP-肽吸引力的进一步增加降低了淀粉样蛋白原纤维的稳定性，并减少了肽构象变化和自缔合所必需的NP表面上的侧向扩散，从而阻止淀粉样蛋白聚集。此外，我们发现蛋白质和纳米颗粒之间的相对浓度也起着重要的作用，淀粉样蛋白聚集。在高NP/蛋白质比率的情况下，固有地促进蛋白质聚集的NP可以通过耗尽溶液中的蛋白质而在每个NP的表面上具有低浓度的蛋白质来显示抑制作用。我们的粗粒度的分子动力学模拟研究提供了一个分子机制，描绘的对比和看似矛盾的影响NP-蛋白质的吸引力对淀粉样蛋白聚集，并强调了定制抗聚集纳米药物对淀粉样蛋白疾病的潜力。
Nanoparticles (NPs) have been experimentally found to either promote or inhibit amyloid aggregation of proteins, but the molecular mechanisms for such complex behaviors remain unknown. Using coarse-grained molecular dynamics simulations, we investigated the effects of varying the strength of nonspecific NP-protein attraction on amyloid aggregation of a model protein, the amyloid-beta peptide implicated in Alzheimer's disease. Specifically, with increasing NP-peptide attraction, amyloid aggregation on the NP surface was initially promoted due to increased local protein concentration on the surface and destabilization of the folded state. However, further increase of NP-peptide attraction decreased the stability of amyloid fibrils and reduced their lateral diffusion on the NP surface necessary for peptide conformational changes and self-association, thus prohibiting amyloid aggregation. Moreover, we found that the relative concentration between protein and NPs also played an important role in amyloid aggregation. With a high NP/protein ratio, NPs that intrinsically promote protein aggregation may display an inhibitive effect by depleting the proteins in solution while having a low concentration of the proteins on each NP's surface. Our coarse-grained molecular dynamics simulation study offers a molecular mechanism for delineating the contrasting and seemingly conflicting effects of NP-protein attraction on amyloid aggregation and highlights the potential of tailoring anti-aggregation nanomedicine against amyloid diseases.