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

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.