Abstract:
Extracellular plaques, the hallmark of Alzheimer\'s disease brains, consist of insoluble amyloid fibrils that result from the aggregation of amyloid beta peptides. None of the few therapeutic options currently adopted, address the cause of the disease. Instead, they reduce symptom of the disease. Inhibition of aggregation or destabilization of aggregates therefore, emerges as a preferable therapeutic approach. Designing inhibitors or destabilizers demands comprehensive knowledge of the residues of amyloid beta responsible for the phenomenal structural stability of the aggregate. For the purpose, we have compared the effect on structural destabilization of 13 in silico mutations (single and double) with the wild type counterpart of beta-strand-turn-beta-strand motif of the amyloid beta protofibrils by molecular dynamics simulation. Besides the already known salt bridge interaction between K28 and D23, our analyses expose more significant role of K28 as the only positive charge present in the vicinity. Amongst the two consecutive aromatic residues, F19 is involved in stacking interaction; although effect of F20 mutation is more pronounced. Face to face arrangement of A21 and V36 acts as a pillar maintaining the necessary optimum distance between consecutive chains to promote stabilizing interactions. In addition to providing stability to the first beta-strand, large sized negatively charged E22 facilitates salt bridge formation by ensuring fixed relative position of D23 and in turn K28. Likewise, the hydrophobic residues I32 and L34 pack the protofibril core, once again fostering salt bridge interaction. Prospectively, these findings may be compiled for efficient identification or design of scaffolds accountable for protofibril destabilization.Communicated by Ramaswamy H. Sarma.
摘要:
细胞外斑块,阿尔茨海默病大脑的标志,由淀粉样β肽聚集产生的不溶性淀粉样原纤维组成。目前采用的少数治疗选择都没有,解决疾病的原因。相反,它们减少了疾病的症状。因此,抑制聚集体的聚集或不稳定,作为一种优选的治疗方法出现。设计抑制剂或去稳定剂需要对β淀粉样蛋白残基的全面了解,这些残基负责聚集体的显着结构稳定性。出于目的,我们通过分子动力学模拟比较了淀粉样蛋白β原原纤维的β-链-转角-β-链基序的13个芯片突变(单和双)与野生型对应物对结构不稳定的影响.除了已知的K28和D23之间的盐桥相互作用之外,我们的分析揭示了K28作为附近存在的唯一正电荷的更重要的作用。在两个连续的芳香残基中,F19参与堆叠相互作用;尽管F20突变的影响更明显。A21和V36的面对面布置充当支柱,维持连续链之间的必要最佳距离以促进稳定相互作用。除了为第一β链提供稳定性外,大尺寸的带负电荷的E22通过确保D23和K28的固定相对位置来促进盐桥形成。同样,疏水残基I32和L34包装原纤核,再次促进盐桥互动。Prospective,这些发现可用于有效鉴定或设计导致原原纤维不稳定的支架。由RamaswamyH.Sarma沟通。