Large scale peptide screening against main protease of SARS CoV-2.

The COVID-19 pandemic has been a public health emergency, with deadly forms constantly emerging around the world, highlighting the dire need for highly effective antiviral therapeutics. Peptide therapeutics show significant potential for this viral disease due to their efficiency, safety, and specificity. Here, two thousand seven hundred eight antibacterial peptides were screened computationally targeting the Main protease (Mpro) of SARS CoV-2. Six top-ranked peptides according to their binding scores, binding pose were investigated by molecular dynamics to explore the interaction and binding behavior of peptide-Mpro complexes. The structural and energetic characteristics of Mpro-DRAMP01760 and Mpro-DRAMP01808 complexes fluctuated less during a 250 ns MD simulation. In addition, three peptides (DRAMP01760, DRAMP01808, and DRAMP01342) bind strongly to Mpro protein, according to the free energy landscape and principal component analysis. Peptide helicity and secondary structure analysis are in agreement with our findings. Interaction analysis of protein-peptide complexes demonstrated that Mpro's residue CYS145, HIS41, PRO168, GLU166, GLN189, ASN142, MET49, and THR26 play significant contributions in peptide-protein attachment. Binding free energy analysis (MM-PBSA) demonstrated the energy profile of interacting residues of Mpro in peptide-Mpro complexes. To summarize, the peptides DRAMP01808 and DRAMP01760 may be highly Mpro specific, resulting disruption in a viral replication and transcription. The results of this research are expected to assist future research toward the development of antiviral peptide-based therapeutics for Covid-19 treatment.

Elucidating the Structure, Dynamics, and Interaction of a Choline Chloride and Citric Acid Based Eutectic System by Spectroscopic and Molecular Modeling Investigations.

Eutectic solvent systems are versatile solvents that have found widespread use in numerous applications. Traditional solvents are homogeneous, having only one component, and their chemistry is relatively simple, with some exceptions. On the other hand, deep eutectic solvents (DESs) comprise binary components, generally a donor and an acceptor in hydrogen bonding with varying ratios. The interaction chemistry among the donor and acceptor involved in hydrogen bonding in DESs is complicated. Although numerous research is focused on the synthesis and application of DESs, few studies are reported to elucidate the complex structure and dynamic and interaction behavior of DESs. In this study, we employed calorimetry, vibrational spectroscopy techniques including FTIR and Raman, and nuclear magnetic resonance to derive insight into the structural feature and noncovalent contact of choline chloride (ChCl) and citric acid (CA) while they formed DESs. The 1:1 ChCl/CA eutectic system showed phase transitions and melting peaks with the most pronounced peak at 156.22 °C, suggesting the DESs melting at a lower temperature than the melting temperatures of ChCl and CA. In addition to IR and Raman findings, 1H NMR investigations demonstrate hydrogen bonding intermolecular interactions between ChCl and CA, supporting the formation of 1:1 ChCl/CA DESs based on the deshielded chemical shifts of the proton for Ch. The interaction of the chloride anion with the methyl protons (H4) and methylene protons (H3) of ChCl as well as the strong hydrogen bonding interactions between the hydroxyl hydrogen (H1) of ChCl with one of CA's carbonyl oxygens both supported the formation of conformer E. In addition, molecular dynamics followed by the density functional theory (DFT) was employed to visualize the structure and interaction of DESs using the ωB97XD theory and 6-311++G (d,p) basis set. Both experimental and theoretical IR, Raman, and structural analyses provided evidence of the formation of DESs by possessing hydrogen bonds. These multifaceted experimental and computational investigations provide details of structural and intermolecular interactions of ChCl/CA DESs.

Structure and dynamics of whole-sequence homology model of ORF3a protein of SARS-CoV-2: An insight from microsecond molecular dynamics simulations.

The ORF3a is a large accessory protein in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which plays an important role in virulence and viral replication; especially in inflammasome activation and apoptosis. However,, the existing cryo-EM structure of SARS-CoV-2 ORF3a is incomplete, . making it challenging to understand its structural and functional features. The aim of this study is to investigate the dynamic behaviors of the full-sequence homology model of ORF3a and compare it with the cryo-EM structure using microsecond molecular dynamics simulations. The previous studies indicated that the unresolved residues of the cryo-EM structure are not only involved in the pathogenesis of the SARS-CoV-2 but also exhibit a significant antigenicity. The dynamics scenario of homology model revealed higher RMSD, Rg, and SASA values with stable pattern when compared to the cryo-EM structure. Moreover, the RMSF analysis demonstrated higher fluctuations at specific positions (1-43, 97-110, 172-180, 219-243) in the model structure, whereas the cryo-EM structure displayed lower overall drift (except 1-43) in comparison to the model structure.Secondary structural features indicated that a significant unfolding in the transmembrane domains and ß-strand at positions 166 to 172, affecting the stability and compactness of the cryo-EM structure , whereas the model exhibited noticeable unfolding in transmembrane domains and small-coiled regions in the N-terminal. , The results from molecular docking and steered molecular dynamics investigations showed the model structure had a greater number of non-bonding interactions, leading to enhanced stability when compared to the cryo-EM structure. Consequently, higher forces were necessary for unbinding of the baricitinib and ruxolitinib inhibitors from the model structure.. Our findings can help better understanding of the significance of unresolved residues at the molecular level. Additionally, this information can guide researchers for experimental endeavors aimed at completing the full-sequence structure of the ORF3a.Communicated by Ramaswamy H. Sarma.