Molecular Modelling and Simulation Laboratory, Department of Molecular Biology and Biotechnology, Tezpur University, Tezpur, Assam, India.
J Biomol Struct Dyn. 2021 Mar;39(4):1334-1342. doi: 10.1080/07391102.2020.1730970. Epub 2020 Mar 2.
Alzheimer's disease (AD) is the most common progressive neurodegenerative brain disorder. It is characterized by the presence of extracellular aggregated fibrillary form of amyloid beta (Aβ) peptide and intraneuronal neurofibrillary tangles caused by the hyperphosphorylation of tau protein. Monomeric form of Aβ peptide in α-conformation is not toxic but it can undergo self-aggregation to form β-conformation which is neurotoxic. The most promising approach to combat AD is to prevent the self-aggregation of Aβ peptide. Recently, it has been reported that C-terminal (CTerm) of human albumin (HA) binds to the Aβ peptide and impairs the Aβ aggregation and promotes disassembly of Aβ aggregates. In this work, using potential of mean force (PMF) and binding free energy (BFE) calculations, we have demonstrated the effect of CTerm of HA on the dimerization of Aβ peptide. From the PMF profile, we noticed Aβ-CTerm Heterodimer (10.99 kcal mol - 1) complex to have higher disassociation energy than Aβ-Aβ homodimer (2.23 kcal mol - 1) complex. And also from the BFE calculations, we found that the binding affinity between Aβ peptide and CTerm (ΔG = -32.27 kcal mol - 1 from MM-GBSA and ΔG = -2.83 kcal mol - 1 from MM-PBSA (molecular mechanics-Poisson - Boltzmann surface area)) to be stronger than the Aβ peptide and another Aβ peptide (ΔG = -16.20 kcal mol - 1 from MM-GBSA and ΔG = -1.95 kcal mol - 1 from MM-PBSA). In this study, our findings from PMF and BFE analysis of the two complexes provide salient structural, binding and unbinding features and thermodynamics that support the ability of CTerm of HA in affecting the dimerization of Aβ. Communicated by Ramaswamy H. Sarma.
阿尔茨海默病（AD）是最常见的进行性神经退行性脑疾病。其特征是存在细胞外聚集的纤维状形式的淀粉样β（Aβ）肽和由tau 蛋白过度磷酸化引起的神经元内神经原纤维缠结。单体形式的 Aβ 肽在α构象下没有毒性，但它可以自行聚集形成β构象，从而具有神经毒性。对抗 AD 最有前途的方法是防止 Aβ 肽的自聚集。最近，据报道，人白蛋白（HA）的 C 端（CTerm）与 Aβ 肽结合，可损害 Aβ 聚集并促进 Aβ 聚集体的解体。在这项工作中，我们使用平均力势（PMF）和结合自由能（BFE）计算，证明了 HA 的 CTerm 对 Aβ 肽二聚化的影响。从 PMF 轮廓中，我们注意到 Aβ-CTerm 杂二聚体（10.99 kcal mol - 1）复合物的离解能高于 Aβ-Aβ 同源二聚体（2.23 kcal mol - 1）复合物。并且，从 BFE 计算中，我们发现 Aβ 肽与 CTerm 之间的结合亲和力（MM-GBSA 中的ΔG = -32.27 kcal mol - 1，MM-PBSA 中的ΔG = -2.83 kcal mol - 1）强于 Aβ 肽与另一个 Aβ 肽（MM-GBSA 中的ΔG = -16.20 kcal mol - 1，MM-PBSA 中的ΔG = -1.95 kcal mol - 1）。在这项研究中，我们从 PMF 和 BFE 对两个复合物的分析中得出的结果提供了明显的结构、结合和非结合特征以及热力学特征，这些特征支持 HA 的 CTerm 影响 Aβ 二聚化的能力。由 Ramaswamy H. Sarma 传达。
