In silico Investigation on the Structural Insights into the Binding of Squalamine Inhibitor with Membrane-Bound Α-Synuclein

Abstract

Background: Parkinson's disease (PD) and its associated symptoms are closely associated with the self-assembly of α-Synuclein (α-Syn). Squalamine is a naturally occurring chemical substance with established antiviral and anticancer properties, and its profound impact on the α- Syn aggregation both in vivo and in vitro is well studied. Examining its interaction with lipid vesicles, which are known to encourage nucleation, can signify the mechanism of action of squalamine. The squalamine molecule is believed to displace α-Syn from the surfaces of the lipid vesicles, therefore preventing the initial steps in the process of aggregation. Additionally, the squalamine molecule reduces the harmful effects of α-Syn oligomers in human neuroblastoma cells by preventing them from interacting with lipid membranes. Objective: The aim of this study was to perform computational investigation of the conformational changes of membrane-bound α-Syn in the presence of squalamine inhibitor molecule objective: Computational investigation of the conformational changes of membrane-bound α-Synuclein in the presence of squalamine inhibitor molecule Method: Molecular Dynamics (MD) trajectory analysis was carried out to study the structural change of the α-Syn-squalamine conformers as a function of simulation time. The percentage of the secondary structural components of the α-Syn-squalamine complex was determined. Optimization of small molecule inhibitors was carried out using Density Functional Theory (DFT) analysis. Additionally, the values of electrophilicity (ω), nucleophilicity (N), Electron affinity (EA), and ionization potential (IP) were calculated. Results: The docking of the α-Syn-squalamine complex revealed the binding site and the best structure was selected based on the highest docking vina score (-5.8), and the contact residues were listed. From the conformational snapshots of the α-Syn-squalamine complex, it was evident that the α-Syn remained stable, maintaining its integrity throughout the simulation. The α-helical content was found to be retained from the secondary structural content analysis. The ω and N of the squalamine molecule were calculated to be -0.84 and 3.25, respectively. Conclusion: Our findings suggest that in the presence of a squalamine inhibitor molecule, α-Syn adopts a helical conformation that ensures stability and may indicate that the squalamine molecule causes gradual displacement of α-Syn across different regions within the lipid membrane.