Melquiond Adrien, Boucher Geneviève, Mousseau Normand, Derreumaux Philippe
Laboratoire de Biochimie Théorique, UPR 9080 CNRS, Institut de Biologie Physico-Chimique et Université Paris 7, France.
J Chem Phys. 2005 May 1;122(17):174904. doi: 10.1063/1.1886725.
There is experimental evidence suggesting that the toxicity of neurodegenerative diseases such as Alzheimer's disease may result from the soluble intermediate oligomers. It is therefore important to characterize extensively the early steps of oligomer formation at atomic level. As these structures are metastable and short lived, experimental data are difficult to obtain and they must be complemented with numerical simulations. In this work, we use the activation-relaxation technique coupled with a coarse-grained energy model to study in detail the mechanisms of aggregation of four lys-phe-phe-glu (KFFE) peptides. This is the shortest peptide known to form amyloid fibrils in vitro. Our simulations indicate that four KFFE peptides adopt a variety of oligomeric states (tetramers, trimers, and dimers) with various orientations of the chains in rapid equilibrium. This conformational distribution is consistent with all-atom molecular-dynamics simulations in explicit solvent and is sequence dependent; as seen experimentally, the lys-pro-gly-glu (KPGE) peptides adopt disordered structures in solution. Our unbiased simulations also indicate that the assembly process is much more complex than previously thought and point to intermediate structures which likely are kinetic traps for longer chains.
有实验证据表明，诸如阿尔茨海默病等神经退行性疾病的毒性可能源于可溶性中间寡聚体。因此，在原子水平上广泛表征寡聚体形成的早期步骤非常重要。由于这些结构是亚稳态且寿命短暂的，实验数据难以获得，必须辅以数值模拟。在这项工作中，我们使用激活-弛豫技术结合粗粒度能量模型，详细研究了四种赖氨酰-苯丙氨酰-苯丙氨酰-谷氨酸（KFFE）肽的聚集机制。这是已知在体外形成淀粉样纤维的最短肽。我们的模拟表明，四条KFFE肽以各种链取向处于快速平衡状态，呈现出多种寡聚状态（四聚体、三聚体和二聚体）。这种构象分布与在明确溶剂中的全原子分子动力学模拟一致，并且依赖于序列；如实验所见，赖氨酰-脯氨酰-甘氨酰-谷氨酸（KPGE）肽在溶液中呈现无序结构。我们的无偏模拟还表明，组装过程比以前认为的要复杂得多，并指出了中间结构，这些结构可能是较长链的动力学陷阱。
