Computational investigation on the conformational dynamics of C-terminal truncated α-synuclein bound to membrane.

Accelerated progression rates in Parkinson's disease (PD) have been linked to C-terminal domain (CTD) truncations of monomeric α-Synuclein (α-Syn), which have been suggested to increase amyloid aggregation in vivo and in vitro. In the brain of PD patients, CTD truncated α-Syn was found to have lower cell viability and tends to increase in the formation of fibrils. The CTD of α-Syn acts as a guard for regulating the normal functioning of α-Syn. The absence of the CTD may allow the N-terminal of α-Syn to interact with the membrane thereby affecting the normal functioning of α-Syn, and all of which will affect the etiology of PD. In this study, the conformational dynamics of CTD truncated α-Syn (1-99 and 1-108) monomers and their effect on the protein-membrane interactions were demonstrated using the all-atom molecular dynamics (MD) simulation method. From the MD analyses, it was noticed that among the two truncated monomers, α-Syn (1-108) was found to be more stable, shows rigidness at the N-terminal region and contains a significant number of intermolecular hydrogen bonds between the non-amyloid ß-component (NAC) region and membrane, and lesser number of extended strands. Further, the bending angle in the N-terminal domain was found to be lesser in the α-Syn (1-108) in comparison with the α-Syn (1-99). Our findings suggest that the truncation on the CTD of α-Syn affects its interaction with the membrane and subsequently has an impact on the aggregation.Communicated by Ramaswamy H. Sarma.

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

Parkinson's disease (PD) is associated with α-synuclein (α-Syn), a presynaptic protein that binds to cell membranes. The molecular pathophysiology of PD most likely begins with the binding of α-Syn to membranes. Recently, two peptidomimetic inhibitors (NPT100-18A and NPT200-11) were identified to potentially interact with α-Syn and affect the interaction of α-Syn with the membrane. In this study, the effect of the two peptidomimetic inhibitors on the α-Syn-membrane interaction was demonstrated. DFT calculations were performed for optimization of the two inhibitors, and the nucleophilicity (N) and electrophilicity (ω) of NPT100-18A and NPT200-11 were calculated to be 3.90 and 3.86 (N); 1.06 and 1.04 (ω), respectively. Using the docking tool (CB-dock2), the two α-Syn-peptidomimetic inhibitor complexes (α-Syn-NPT100-18A and α-Syn-NPT200-11) have been prepared. Then all-atom molecular dynamics (MD) simulation was carried out on the α-Syn (control), α-Syn-NPT100-18A and α-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 α-Syn was found to be stable, and the helices present in the regions (1-37) and (45-95) of α-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 α-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 α-Syn-membrane interactions may be useful for developing a new therapeutic approach for treating PD and other neurodegenerative disorders.Communicated by Ramaswamy H. Sarma.

Identification of FDA-approved drugs with triple targeting mode of action for the treatment of monkeypox: a high throughput virtual screening study.

According to the Center for Disease Control and Prevention, as of August 23, 94 countries had confirmed 42,954 Monkeypox Virus cases. As specific monkeypox drugs are not yet developed, the treatment depends on repurposed FDA-approved drugs. According to a recent study, the Monkeypox outbreak is caused by a strain with a unique mutation, raising the likelihood that the virus will develop resistance to current drugs by acquiring mutations in the targets of currently used drugs. The probability of multiple mutations in two or more drug targets at a time is always low than mutation in a single drug target. Therefore, we identified 15 triple-targeting FDA-approved drugs that can inhibit three viral targets, including topoisomerase1, p37, and thymidylate kinase, using high throughput virtual screening approach. Further, the molecular dynamics simulation analysis of the top hits such as Naldemedine and Saquinavir with their respective targets reveals the formation of stable conformational changes of the ligand-protein complexes inside the dynamic biological environment. We suggest further research on these triple-targeting molecules to develop an effective therapy for the currently spreading Monkeypox.

Conformational dynamics of A30G α-synuclein that causes familial Parkinson disease.

The first gene shown to be responsible for autosomal-dominant Parkinson's disease (PD) is the SNCA gene, which encodes for alpha synuclein (α-Syn). Recently, a novel heterozygous A30G mutation of the SNCA gene associated with familial PD has been reported. However, little research has been done on how the A30G mutation affects the structure of α-Syn. So, using atomistic molecular dynamics (MD) simulation, we demonstrate here the key structural characteristics of A30G α-Syn in the free monomer form and membrane associated state. From the MD trajectory analysis, the structure of A30G α-Syn was noticed to exhibit rapid conformational change, increase in backbone flexibility near the site of mutation and decrease in α-helical propensity. The typical torsion angles in residues (Val26 and Glu28) near the mutation site were observed to deviate significantly in A30G α-Syn. In the case of membrane bound A30G α-Syn, the regions that were submerged in the lipid bilayer (N-helix (3-37) and turn region (38-44)) found to contain higher helical content than the elevated region above the lipid surface. The bending angle in the helix-N and helix-C regions were noticed to be relatively higher in the free form of A30G α-Syn (38.50) than in the membrane bound form (370). The A30G mutation in α-Syn was predicted to have an impact on the stability and function of the protein based on ΔΔG values obtained from the online servers. Our results demonstrate that the A30G mutation in α-Syn altered the protein's α-helical structure and slightly altered the membrane binding.Communicated by Ramaswamy H. Sarma.