King Kelsie M, Sharp Amanda K, Davidson Darcy S, Brown Anne M, Lemkul Justin A
Program in Genetics, Bioinformatics, and Computational Biology, Virginia Tech, 340 West Campus Dr, Blacksburg, VA 24060, USA.
Department of Biochemistry, Virginia Tech, 340 West Campus Dr, Blacksburg, VA 24060, USA.
J Comput Biophys Chem. 2022 Jun;21(4):449-460. doi: 10.1142/s2737416521420059. Epub 2021 Dec 29.
Amyloids are a subset of intrinsically disordered proteins (IDPs) that self-assemble into cross-β oligomers and fibrils. The structural plasticity of amyloids leads to sampling of metastable, low-molecular-weight oligomers that contribute to cytotoxicity. Of interest are amyloid-β (Aβ) and islet amyloid polypeptide (IAPP), which are involved in the pathology of Alzheimer's disease and Type 2 Diabetes Mellitus, respectively. In addition to forming homogenous oligomers and fibrils, these species have been found to cross-aggregate in heterogeneous structures. Biophysical properties, including electronic effects, that are unique or conserved between homogenous and heterogenous amyloids oligomers are thus far unexplored. Here, we simulated homogenous and heterogenous amyloid oligomers of Aβ and IAPP fragments using the Drude oscillator model to investigate the impact of electronic polarization on the structural morphology and stability of preformed hexamers. Upon simulation of preformed, β-strand rich oligomers with Drude, structural rearrangement occurred causing some loss of β-strand structure in favor of random coil content for all oligomers. Homogenous Aβ was the most stable system, deriving stability from low polarization in hydrophobic residues and through salt bridge formation. Changes in polarization were observed primarily for Aβ residues in heterogenous cross-amyloid systems, displaying a decrease in charged residue dipole moments and an increase in hydrophobic sidechain dipole moments. This work is the first study utilizing the Drude-2019 force field with amyloid oligomers, providing insight into the impact of electronic effects on oligomer structure and highlighting the importance of different microenvironments on amyloid oligomer stability.
淀粉样蛋白是内在无序蛋白质（IDP）的一个子集，可自组装成交叉β寡聚体和纤维。淀粉样蛋白的结构可塑性导致对亚稳态低分子量寡聚体的采样，这些寡聚体促成细胞毒性。值得关注的是淀粉样β蛋白（Aβ）和胰岛淀粉样多肽（IAPP），它们分别与阿尔茨海默病和2型糖尿病的病理过程有关。除了形成同质寡聚体和纤维外，还发现这些物质会在异质结构中交叉聚集。到目前为止，尚未探索同质和异质淀粉样寡聚体之间独特或保守的生物物理性质，包括电子效应。在这里，我们使用德鲁德振子模型模拟了Aβ和IAPP片段的同质和异质淀粉样寡聚体，以研究电子极化对预先形成的六聚体的结构形态和稳定性的影响。在用德鲁德模型模拟预先形成的富含β链的寡聚体时，发生了结构重排，导致所有寡聚体的β链结构有所损失，转而有利于无规卷曲含量。同质Aβ是最稳定的系统，其稳定性源于疏水残基的低极化以及盐桥的形成。在异质交叉淀粉样系统中，主要观察到Aβ残基的极化变化，表现为带电残基偶极矩减小，疏水侧链偶极矩增加。这项工作是首次利用德鲁德 - 2019力场对淀粉样寡聚体进行研究，深入了解了电子效应对寡聚体结构的影响，并突出了不同微环境对淀粉样寡聚体稳定性的重要性。
