scholarly journals Predicting spike protein NTD mutations of SARS-CoV-2 causing immune escape by molecular dynamics simulations

Author(s):  
Liping Zhou ◽  
Leyun Wu ◽  
Cheng Peng ◽  
Yanqing Yang ◽  
Yulong Shi ◽  
...  
Author(s):  
Liping Zhou ◽  
Leyun Wu ◽  
Cheng Peng ◽  
Yanqing Yang ◽  
Yulong Shi ◽  
...  

The coronavirus disease 2019 (COVID-19) pandemic is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Among all the potential targets studied for developing drugs and antibodies, the spike (S)...


Author(s):  
Stefano Serapian ◽  
Filippo Marchetti ◽  
Alice Triveri ◽  
Giulia Morra ◽  
Massimiliano Meli ◽  
...  

AbstractBetacoronavirus SARS-CoV-2 is posing a major threat to human health and its diffusion around the world is having dire socioeconomical consequences. Thanks to the scientific community’s unprecedented efforts, the atomic structure of several viral proteins has been promptly resolved. As the crucial mediator of host cell infection, the heavily glycosylated trimeric viral Spike protein (S) has been attracting the most attention and is at the center of efforts to develop antivirals, vaccines, and diagnostic solutions.Herein, we use an energy-decomposition approach to identify antigenic domains and antibody binding sites on the fully glycosylated S protein. Crucially, all that is required by our method are unbiased atomistic molecular dynamics simulations; no prior knowledge of binding properties or ad hoc combinations of parameters/measures extracted from simulations is needed. Our method simply exploits the analysis of energy interactions between all intra-protomer aminoacid and monosaccharide residue pairs, and cross-compares them with structural information (i.e., residueresidue proximity), identifying potential immunogenic regions as those groups of spatially contiguous residues with poor energetic coupling to the rest of the protein.Our results are validated by several experimentally confirmed structures of the S protein in complex with anti- or nanobodies. We identify poorly coupled sub-domains: on the one hand this indicates their role in hosting (several) epitopes, and on the other hand indicates their involvement in large functional conformational transitions. Finally, we detect two distinct behaviors of the glycan shield: glycans with stronger energetic coupling are structurally relevant and protect underlying peptidic epitopes; those with weaker coupling could themselves be poised for antibody recognition. Predicted Immunoreactive regions can be used to develop optimized antigens (recombinant subdomains, synthetic (glyco)peptidomimetics) for therapeutic applications.


2021 ◽  
Vol 8 ◽  
Author(s):  
Sugunadevi Sakkiah ◽  
Wenjing Guo ◽  
Bohu Pan ◽  
Zuowei Ji ◽  
Gokhan Yavas ◽  
...  

Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19). As of October 21, 2020, more than 41.4 million confirmed cases and 1.1 million deaths have been reported. Thus, it is immensely important to develop drugs and vaccines to combat COVID-19. The spike protein present on the outer surface of the virion plays a major role in viral infection by binding to receptor proteins present on the outer membrane of host cells, triggering membrane fusion and internalization, which enables release of viral ssRNA into the host cell. Understanding the interactions between the SARS-CoV-2 trimeric spike protein and its host cell receptor protein, angiotensin converting enzyme 2 (ACE2), is important for developing drugs and vaccines to prevent and treat COVID-19. Several crystal structures of partial and mutant SARS-CoV-2 spike proteins have been reported; however, an atomistic structure of the wild-type SARS-CoV-2 trimeric spike protein complexed with ACE2 is not yet available. Therefore, in our study, homology modeling was used to build the trimeric form of the spike protein complexed with human ACE2, followed by all-atom molecular dynamics simulations to elucidate interactions at the interface between the spike protein and ACE2. Molecular Mechanics Poisson-Boltzmann Surface Area (MMPBSA) and in silico alanine scanning were employed to characterize the interacting residues at the interface. Twenty interacting residues in the spike protein were identified that are likely to be responsible for tightly binding to ACE2, of which five residues (Val445, Thr478, Gly485, Phe490, and Ser494) were not reported in the crystal structure of the truncated spike protein receptor binding domain (RBD) complexed with ACE2. These data indicate that the interactions between ACE2 and the tertiary structure of the full-length spike protein trimer are different from those between ACE2 and the truncated monomer of the spike protein RBD. These findings could facilitate the development of drugs and vaccines to prevent SARS-CoV-2 infection and combat COVID-19.


2022 ◽  
Author(s):  
Emine Deniz Tekin

We perform all-atom molecular dynamics simulations to study the effects of the N-linked glycans on the stability of the spike glycoprotein in SARS-CoV-2. After a 100 ns of simulation on the spike proteins without and with the N-linked glycans, we found that the presence of glycans increases the local stability in their vicinity; even though their effect on the full structure is negligible.


2021 ◽  
Vol 2021 ◽  
pp. 1-19
Author(s):  
Arshia Majeed ◽  
Waqar Hussain ◽  
Farkhanda Yasmin ◽  
Ammara Akhtar ◽  
Nouman Rasool

The recent COVID-19 pandemic has impacted nearly the whole world due to its high morbidity and mortality rate. Thus, scientists around the globe are working to find potent drugs and designing an effective vaccine against COVID-19. Phytochemicals from medicinal plants are known to have a long history for the treatment of various pathogens and infections; thus, keeping this in mind, this study was performed to explore the potential of different phytochemicals as candidate inhibitors of the HR1 domain in SARS-CoV-2 spike protein by using computer-aided drug discovery methods. Initially, the pharmacological assessment was performed to study the drug-likeness properties of the phytochemicals for their safe human administration. Suitable compounds were subjected to molecular docking to screen strongly binding phytochemicals with HR1 while the stability of ligand binding was analyzed using molecular dynamics simulations. Quantum computation-based density functional theory (DFT) analysis was constituted to analyze the reactivity of these compounds with the receptor. Through analysis, 108 phytochemicals passed the pharmacological assessment and upon docking of these 108 phytochemicals, 36 were screened passing a threshold of -8.5 kcal/mol. After analyzing stability and reactivity, 5 phytochemicals, i.e., SilybinC, Isopomiferin, Lycopene, SilydianinB, and Silydianin are identified as novel and potent candidates for the inhibition of HR1 domain in SARS-CoV-2 spike protein. Based on these results, it is concluded that these compounds can play an important role in the design and development of a drug against COVID-19, after an exhaustive in vitro and in vivo examination of these compounds, in future.


2020 ◽  
Author(s):  
Dr. Chirag N. Patel ◽  
Dr. Prasanth Kumar S. ◽  
Dr. Himanshu A. Pandya ◽  
Dr. Rakesh M. Rawal

<p>The pandemic outbreak of COVID-19 virus (SARS-CoV-2) has become critical global health issue. The biophysical and structural evidence shows that SARS-CoV-2 spike protein possesses higher binding affinity towards angiotensin-converting enzyme 2 (ACE2) and hemagglutinin-acetylesterase (HE) glycoprotein receptor. Hence, it was selected as a target to generate the potential candidates for the inhibition of HE glycoprotein. The present study focuses on extensive computational approaches which contains molecular docking, ADMET prediction followed by molecular dynamics simulations and free energy calculations. Furthermore, virtual screening of NPACT compounds identified 3,4,5-Trihydroxy-1,8-bis[(2R,3R)-3,5,7-trihydroxy-3,4-dihydro-2H-chromen-2-yl]benzo[7]annulen-6-one, Silymarin, Withanolide D, Spirosolane and Oridonin were interact with high affinity. The ADMET prediction revealed pharmacokinetics and drug-likeness properties of top-ranked compounds. Molecular dynamics simulations and binding free energy calculations affirmed that these five NPACT compounds were robust HE inhibitor.</p>


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