Aβ_(37-42)形成二聚体的分子模拟研究

Dimerization of Aβ_(37-42) Studied by the Molecular Simulations

阿尔茨海默症是一种神经退行性疾病,多发病于老年人群.该疾病不但严重影响患者的健康及正常生活,还给患者家属带来极大痛苦.因此治疗该疾病成为科学界急欲攻克的难关.而治疗的基础是解析病理,大量研究表明该病患者脑内有大量纤维状Aβ蛋白质聚集物.因此研究Aβ蛋白质如何聚集是解析病理的关键.同时预防和阻止Aβ蛋白质聚集也成为治疗阿尔茨海默症的一种可选方案.本文即选取Aβ蛋白质片段,以分子动力学模拟方法,详细分析其形成稳定二聚体的完整过程.研究发现该蛋白质片段上残基侧链之间的疏水作用促使两个Aβ37-42单体相互靠近,其间会形成多种非稳态中间体,其结构经过不断调整最终才形成稳定的二聚体结构.该结构调整过程对形成稳定的二聚体结构非常重要.在此过程中两条肽链主链形成氢键的个数逐渐增加,同时伴随形成了新的残基侧链之间的相互作用.研究发现在二聚体形成的全过程中Ile41和Ala42均起到不可忽视的作用.Ile41由于其侧链具有疏水性且体积相对较大,可通过其疏水作用力促使两个单体相互靠近.而Ala42在后期结构调整中发挥了一定作用,稳定了二聚体的结构.该研究有助于更好地理解Aβ蛋白质聚集特别是其形成二聚体的过程,同时也为防治Aβ蛋白质聚集提供了一些理论依据.

Alzheimer＇s disease（AD）is a neurodegenerative disease usually affecting the elderly.AD can seriously affect the normal life of the patients and bring pains to their families.Therefore,scientists have tried hard to find out the solutions that can cure AD.Understanding how the disease is developed is essential for the treatment of AD.Researchers have found that the fibrils made of the amyloidβ（Aβ）peptides are deposited in the brain of the AD patients.Therefore,it is necessary to study the amyloidβpeptide aggregation process.Meanwhile,inhibiting the Aβaggregation process is suggested as one of the possible ways for the treatment of AD.In this paper,we study the dimerization process of Aβ37-42 by the molecular dynamics simulations.We find that the two monomers approach each other due to the favorable hydrophobic interactions between their side chains.The dimerization process undergoes several intermediate states,through which the two chains adjust their interactions and conformations continuously.With the increasing number of the interchain hydrogen bonds and the newly formed side chain interactions,the dimer structure is stabilized finally.We also find that the contributions of Ile41 and Ala42are nonnegligible in this dimerization process.Ile41 helps bring the two monomers close to each other with the aid of its hydrophobic side chain,and Ala42 contributes to the optimization of conformations in the late stage of the dimerization process.This study can help people understand more about the Aβaggregation（especially the dimerization）process and may also provide some clues for the inhibition of the Aβaggregation.