Kelley Nicholas W, Vishal V, Krafft Grant A, Pande Vijay S
Department of Biophysics, Stanford University, Stanford, California 94305, USA.
J Chem Phys. 2008 Dec 7;129(21):214707. doi: 10.1063/1.3010881.
Here, we present a novel computational approach for describing the formation of oligomeric assemblies at experimental concentrations and timescales. We propose an extension to the Markovian state model approach, where one includes low concentration oligomeric states analytically. This allows simulation on long timescales (seconds timescale) and at arbitrarily low concentrations (e.g., the micromolar concentrations found in experiments), while still using an all-atom model for protein and solvent. As a proof of concept, we apply this methodology to the oligomerization of an Abeta peptide fragment (Abeta(21-43)). Abeta oligomers are now widely recognized as the primary neurotoxic structures leading to Alzheimer's disease. Our computational methods predict that Abeta trimers form at micromolar concentrations in 10 ms, while tetramers form 1000 times more slowly. Moreover, the simulation results predict specific intermonomer contacts present in the oligomer ensemble as well as putative structures for small molecular weight oligomers. Based on our simulations and statistical models, we propose a novel mutation to stabilize the trimeric form of Abeta in an experimentally verifiable manner.
在此，我们提出了一种新颖的计算方法，用于描述在实验浓度和时间尺度下寡聚体组装体的形成。我们对马尔可夫状态模型方法进行了扩展，其中通过解析方式纳入了低浓度寡聚体状态。这使得我们能够在长时间尺度（秒级时间尺度）以及任意低浓度（例如实验中发现的微摩尔浓度）下进行模拟，同时仍使用蛋白质和溶剂的全原子模型。作为概念验证，我们将此方法应用于Aβ肽片段（Aβ(21 - 43)）的寡聚化过程。如今，Aβ寡聚体被广泛认为是导致阿尔茨海默病的主要神经毒性结构。我们的计算方法预测，Aβ三聚体在微摩尔浓度下于10毫秒内形成，而四聚体形成速度则慢1000倍。此外，模拟结果预测了寡聚体集合中存在的特定单体间接触以及小分子量寡聚体的假定结构。基于我们的模拟和统计模型，我们提出了一种新颖的突变，以一种可通过实验验证的方式稳定Aβ的三聚体形式。
