基于Asn27脱酰胺化修饰探究抑制Aβ42聚合的潜在作用位点

Exploring potential affected site for the inhibition of Aβ42polymerization based on Asn27 deamidation modification

阿尔茨海默症(Alzheimer’s disease, AD)主要的病理特征表现为β-淀粉样蛋白(amyloid-βprotein, Aβ)在细胞外聚合形成斑块。抑止Aβ分子聚合,阻止Aβ分子聚合形成具有神经毒性的寡聚体是开发治疗AD药物的方向之一。研究表明当Aβ42中Asn27发生脱酰胺化修饰后,能够有效阻止Aβ单体发生聚合,但具体作用机制尚不清楚。针对此问题,本研究采用分子动力学模拟方法,探究Asn27发生脱酰胺修饰对Aβ42单体结构的改变和对聚合的影响。结果表明, Aβ42的Asn27发生脱酰胺化修饰会破坏D23~K28之间形成的盐桥,抑制Turn区域残基形成β转角结构,导致羧基末端(C-terminal region, CTR)与氨基末端(N-terminal region, NTR)区域不能形成反向平行的β折叠,使得Aβ42链内相互作用减弱。Asn27发生脱酰胺化修饰引起结构的改变,导致Aβ42单体间的聚合作用下降,这也与之前的实验结果相符合。D23~K28盐桥的形成对于促进Aβ42单体的聚合具有重要作用,将是针对抑制Aβ42聚合的潜在药物设计位点。

One of pathological features of Alzheimer’s disease(AD) is extracelluar aggregation of amyloid-βprotein(Aβ) forming senile plaques. Investigation on inhibition of Aβ aggregation can be crucial for designing effective drugs against AD. Previous studies have demonstrated that the deamidation at Asn27, a type of post translation modification, significantly prevented the polymerization of Aβ monomers. But the underlying mechanism is still unclear. Therefore, we investigated the possible effect of Asn27 deamidation on structure and aggregation of A β 42 monomer using molecular dynamics simulation. The results showed that the deamidation of Asn27 can directly disrupt the salt bridge formed between D23 and K28, and effectively decrease the content of β-sheet that is important for aggregation of Aβ. Moreover, the inability at C-terminal region(CTR) and N-terminal region(NTR) to form antiparallel β-sheets further weakens the intra-peptide interaction of Aβ42 monomer. These changes caused by Asn27 deamidation lead to the decline of the aggregated trend of Aβ42 monomer, which is consistent with the experimental observation. According to these results, the salt bridge formed between D23 and K28 plays an important role in promoting the polymerization process between Aβ42 monomers, and disrupting this interaction may be a potential direction for further designing drugs to inhibit aggregation of Aβ42. In summary, this study shows a potential affected site that can efficiently inhibit aggregation of Aβ42.