Remarked suppression of Aβ42 protomer-protomer dissociation reaction elucidated by molecular dynamics simulation
Remarked suppression of Aβ42 protomer-protomer dissociation reaction elucidated by molecular dynamics simulation
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分子动力学模拟阐明 Aβ42 原体-原体解离反应的显着抑制
DOI：
10.1002/prot.26319
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发表时间：
2022
期刊：
影响因子：
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通讯作者：
Tanaka Shigenori
中科院分区：
文献类型：
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作者：
Kurisaki Ikuo;Tanaka Shigenori
多聚体蛋白质复合体是调节生物系统的分子装置，常常决定它们的命运。在形成这种分子组合的蛋白质中，淀粉样蛋白引起了半个世纪的关注，因为这些蛋白的淀粉样原纤维的形成被认为是神经退行性疾病的常见致病原因。这一过程是由纤维状聚集体的积累触发的，而由于实验方法的技术限制，在水溶液中单独观察不同的聚集体物种时，微观机制大多难以捉摸。然后，我们通过对聚集性淀粉样蛋白A-β(Aβ42)进行原子分子动力学模拟来解决这个问题。研究了低聚Aβ42纤维状聚集体在水溶液中的7种不同二聚体形式，从四聚体到十聚体。我们发现这些纤维状聚集体的大小对其热力学稳定性的影响是相加的，并阐明了在五聚体形成点和五聚体形成点之外的原-原构体解离反应的动力学抑制。这一观察结果是从Aβ42原构体结构和我们在这里检查的物理化学条件的特定组合中获得的，同时值得回忆的是，几个淀粉样原纤维具有其原构体的二聚体形式。因此，我们可以得出结论，纤维样原二聚体的稳定形成应该参与到一个转折点，在那里淀粉样原纤维的快速生长被触发。
Multimeric protein complexes are molecular apparatuses to regulate biological systems and often determine their fate. Among proteins forming such molecular assemblies, amyloid proteins have drawn attention over a half‐century since amyloid fibril formation of these proteins is supposed to be a common pathogenic cause for neurodegenerative diseases. This process is triggered by the accumulation of fibril‐like aggregates, while the microscopic mechanisms are mostly elusive due to technical limitation of experimental methodologies in individually observing each of diverse aggregate species in the aqueous solution. We then addressed this problem by employing atomistic molecular dynamics simulations for the paradigmatic amyloid protein, amyloid‐β (Aβ42). Seven different dimeric forms of oligomeric Aβ42fibril‐like aggregate in aqueous solution, ranging from tetramer to decamer, were considered. We found additive effects of the size of these fibril‐like aggregates on their thermodynamic stability and have clarified kinetic suppression of protomer‐protomer dissociation reactions at and beyond the point of pentamer dimer formation. This observation was obtained from the specific combination of the Aβ42protomer structure and the physicochemical condition that we here examined, while it is worthwhile to recall that several amyloid fibrils take dimeric forms of their protomers. We could thus conclude that the stable formation of fibril‐like protomer dimer should be involved in a turning point where rapid growth of amyloid fibrils is triggered.