Alzheimer's disease (AD) is a progressive brain disorder. The accumulation of amyloid beta (Aβ) peptides in the human brain leads to AD. The cleavage of Aβ peptides by several enzymes is being considered as an essential aspect in the treatment of AD. Neprilysin (NEP) is an important enzyme that clears the Aβ plaques in the human brain. The human NEP activity has been found reduced due to mutations in NEP and the presence of inhibitors. However, the role of NEP in the degradation of Aβ peptides in detail at the molecular level is not yet clear. Hence, in the present study, we have investigated the structural significance of NEP from the bacterial source Streptococcus suis GZ1 using various bioinformatics approaches. The homology modelling technique was used to predict the three-dimensional structure of NEP. Further, molecular dynamic (MD) simulated model of NEP was docked with Aβ peptide. Analysis of MD simulated docked complex showed that the wild-type NEP-Aβ-peptide complex is more stable as compared to mutant complex. Hydrogen bonding interactions between NEP with Zn²⁺and Aβ peptide confirm the degradation of the Aβ peptide. The molecular docking and MD simulation results revealed that the active site residue Glu-538 of bacterial NEP along with Zn²⁺ interact with His-13 of Aβ peptide. This stable interaction confirms the involvement of NEP with Glu-538 in the degradation of the Aβ peptide. The other residues such as Glu203, Ser537, Gly140, Val587, and Val536 could also play an important role in the cleavage of Aβ peptide in between Asp1-Ala2, Arg5-His6, Val18-Phe19, Gly9-Tyr10, and Arg5-His6. Hence, the predicted model of the NEP enzyme of Streptococcus suis GZ1could be useful to understand the Aβ peptide degradation in detail at the molecular level. The information obtained from this study would be helpful in designing new lead molecules for the effective treatment of AD.

阿尔茨海默病 (AD) 是一种进行性脑部疾病。人脑中淀粉样蛋白 β (Aβ) 肽的积累导致 AD。几种酶对 Aβ 肽的裂解被认为是 AD 治疗的一个重要方面。脑啡肽酶 (NEP) 是一种重要的酶，可清除人脑中的 Aβ 斑块。已发现由于 NEP 突变和抑制剂的存在，人类 NEP 活性降低。然而，NEP在分子水平上详细降解Aβ肽中的作用尚不清楚。因此，在本研究中，我们研究了来自细菌来源猪链球菌 GZ1的 NEP 的结构意义使用各种生物信息学方法。同源建模技术用于预测NEP的三维结构。此外，NEP的分子动力学（MD）模拟模型与Aβ肽对接。MD 模拟对接复合物的分析表明，与突变复合物相比，野生型 NEP-Aβ-肽复合物更稳定。NEP 与 Zn ²⁺和 Aβ 肽之间的氢键相互作用证实了 Aβ 肽的降解。分子对接和MD模拟结果表明，细菌NEP的活性位点残基Glu-538与Zn ²⁺与 Aβ 肽的 His-13 相互作用。这种稳定的相互作用证实了 NEP 与 Glu-538 参与了 Aβ 肽的降解。其他残基如 Glu203、Ser537、Gly140、Val587 和 Val536 也可以在 Asp1-Ala2、Arg5-His6、Val18-Phe19、Gly9-Tyr10 和 Arg5-His6 之间的 Aβ 肽裂解中发挥重要作用。因此，猪链球菌 GZ1的 NEP 酶的预测模型可能有助于在分子水平上详细了解 Aβ 肽的降解。从这项研究中获得的信息将有助于设计有效治疗 AD 的新先导分子。