4.7 Article

Computational investigation on the effect of the peptidomimetic inhibitors (NPT100-18A and NPT200-11) on the α-synuclein and lipid membrane interactions

出版社

TAYLOR & FRANCIS INC
DOI: 10.1080/07391102.2023.2262599

关键词

alpha-Synuclein aggregation; membrane dynamics; DFT; NPT100-18A; NPT200-11

向作者/读者索取更多资源

This study investigated the effect of peptidomimetic inhibitors on the interaction between alpha-Syn and cell membranes. The inhibitors were found to stabilize the structure of alpha-Syn and bind closely to lipid membranes. These findings may have important implications for the development of new therapeutic approaches for Parkinson's disease and other neurodegenerative disorders.
Parkinson's disease (PD) is associated with alpha-synuclein (alpha-Syn), a presynaptic protein that binds to cell membranes. The molecular pathophysiology of PD most likely begins with the binding of alpha-Syn to membranes. Recently, two peptidomimetic inhibitors (NPT100-18A and NPT200-11) were identified to potentially interact with alpha-Syn and affect the interaction of alpha-Syn with the membrane. In this study, the effect of the two peptidomimetic inhibitors on the alpha-Syn-membrane interaction was demonstrated. DFT calculations were performed for optimization of the two inhibitors, and the nucleophilicity (N) and electrophilicity (omega) of NPT100-18A and NPT200-11 were calculated to be 3.90 and 3.86 (N); 1.06 and 1.04 (omega), respectively. Using the docking tool (CB-dock2), the two alpha-Syn-peptidomimetic inhibitor complexes (alpha-Syn-NPT100-18A and alpha-Syn-NPT200-11) have been prepared. Then all-atom molecular dynamics (MD) simulation was carried out on the alpha-Syn (control), alpha-Syn-NPT100-18A and alpha-Syn-NPT200-11 complex systems in presence of DOPE: DOPS: DOPC (5:3:2) lipid bilayer. From the conformational dynamics analysis, the 3-D structure of alpha-Syn was found to be stable, and the helices present in the regions (1-37) and (45-95) of alpha-Syn were found to be retained in the presence of the two peptidomimetic inhibitors. The electron density profile analysis revealed the binding modes of NAC and C-terminal region of alpha-Syn (in the presence of NPT200-11 inhibitor) with lipid membrane are in the close vicinity from the lipid bilayer centre. Our findings in this study on alpha-Syn-membrane interactions may be useful for developing a new therapeutic approach for treating PD and other neurodegenerative disorders.

作者

我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。

评论

主要评分

4.7
评分不足

次要评分

新颖性
-
重要性
-
科学严谨性
-
评价这篇论文

推荐

暂无数据
暂无数据