Khatua Prabir, Sinha Sudipta Kumar, Bandyopadhyay Sanjoy
Molecular Modeling Laboratory, Department of Chemistry, Indian Institute of Technology , Kharagpur 721302, India.
Department of Chemistry, Indian Institute of Technology Ropar , Ropar 140001, India.
J Chem Inf Model. 2017 Sep 25;57(9):2378-2392. doi: 10.1021/acs.jcim.7b00407. Epub 2017 Sep 12.
Alzheimer's disease is caused due to aggregation of amyloid beta (Aβ) peptide into soluble oligomers and insoluble fibrils in the brain. In this study, we have performed room temperature molecular dynamics simulations to probe the size-dependent conformational features and thermodynamic stabilities of five Aβ protofilaments, namely, O (pentamer), O (octamer), O (decamer), O (dodecamer), and O (tetradecamer). Analysis of the free energy profiles of the aggregates showed that the higher order protofilaments (O, O, and O) undergo conformational transitions between two minimum energy states separated by small energy barriers, while the smaller aggregates (O and O) remain in single deep minima surrounded by high barriers. Importantly, it is demonstrated that O is the crossover point for which the twisting of the protofilament is maximum, beyond which the monomers tend to rearrange themselves in an intermediate state and eventually transform into more stable conformations. Our results suggest that the addition of monomers along the axis of an existing protofilament with a critical size (O according to the present study) proceeds via an intermediate step with relatively less stable twisted structure that allows the additional monomers to bind and form stable larger protofilaments with minor rearrangements among themselves. More importantly, it is demonstrated that a combination of twist angle and end-to-end distance can be used as a suitable reaction coordinate to describe the growth mechanism of Aβ protofilaments in simulation studies.
阿尔茨海默病是由淀粉样β（Aβ）肽在大脑中聚集成可溶性寡聚体和不溶性纤维所致。在本研究中，我们进行了室温分子动力学模拟，以探究五种Aβ原纤维，即O（五聚体）、O（八聚体）、O（十聚体）、O（十二聚体）和O（十四聚体）的尺寸依赖性构象特征和热力学稳定性。对聚集体的自由能分布分析表明，高阶原纤维（O、O和O）在由小能量势垒分隔的两个最低能量状态之间经历构象转变，而较小的聚集体（O和O）则保持在由高势垒包围的单个深最小值中。重要的是，已证明O是原纤维扭转最大的交叉点，超过该点，单体倾向于在中间状态重新排列，并最终转变为更稳定的构象。我们的结果表明，沿着具有临界尺寸（根据本研究为O）的现有原纤维轴添加单体是通过具有相对不稳定扭转结构的中间步骤进行的，该中间步骤允许额外的单体结合并形成彼此之间具有微小重排的稳定更大原纤维。更重要的是，已证明扭转角和端到端距离的组合可作为合适的反应坐标，用于在模拟研究中描述Aβ原纤维的生长机制。
