scholarly journals Molecular dynamics analysis of fast-spreading severe acute respiratory syndrome coronavirus 2 variants and their effects in the interaction with human angiotensin-converting enzyme 2

2021 ◽  
Author(s):  
Anacleto Silva de Souza ◽  
Vitor Martins de Freitas Amorim ◽  
Gabriela D. A. Guardia ◽  
Felipe R C dos Santos ◽  
Filipe F dos Santos ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Severe Acute Respiratory Syndrome ◽  
Host Cell ◽  
Proteolytic Enzymes ◽  
Severe Disease ◽  
Host Cells ◽  
Angiotensin Converting Enzyme 2 ◽  
Fast Spreading ◽  
Host Cell Factors ◽  
Dynamics Simulations

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is evolving with mutations in the Spike protein, especially in the receptor-binding domain (RBD). The failure of public health measures to contain the spread of the disease in many countries has given rise to novel viral variants with increased transmissibility. However, key questions about how quickly the variants can spread and whether they can cause a more severe disease remain unclear. Herein, we performed a structural investigation using molecular dynamics simulations and determined dissociation constant (KD) values using surface plasmon resonance (SPR) assays of three fast-spreading SARS-CoV-2 variants, Alpha, Beta and Gamma ones, as well as genetic factors in the host cells that may be related to the viral infection. Our results suggest that the SARS-CoV-2 variants facilitate their entry into the host cell by moderately increased binding affinities to the human ACE2 receptor, different torsions in hACE2 mediated by RBD variants, and an increased Spike exposure time to proteolytic enzymes. We also found that other host cell aspects, such as gene and isoform expression of key genes for the infection (ACE2, FURIN and TMPRSS2), may have few contributions to the SARS-CoV-2 variants infectivity. In summary, we concluded that a combination of viral and host cell factors allows SARS-CoV-2 variants to increase their abilities to spread faster than wild-type.

scholarly journals Elucidating Interactions Between SARS-CoV-2 Trimeric Spike Protein and ACE2 Using Homology Modeling and Molecular Dynamics Simulations

2021 ◽  
Vol 8 ◽  
Author(s):  
Sugunadevi Sakkiah ◽  
Wenjing Guo ◽  
Bohu Pan ◽  
Zuowei Ji ◽  
Gokhan Yavas ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Homology Modeling ◽  
Molecular Dynamics Simulations ◽  
Host Cell ◽  
Tertiary Structure ◽  
Cell Receptor ◽  
Host Cells ◽  
Spike Protein ◽  
Receptor Protein ◽  
Dynamics Simulations

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.

scholarly journals Computational analysis on the ACE2-derived peptides for neutralizing the ACE2 binding to the spike protein of SARS-CoV-2

2020 ◽  
Author(s):  
Cecylia S. Lupala ◽  
Vikash Kumar ◽  
Xuanxuan Li ◽  
Xiao-dong Su ◽  
Haiguang Liu
Keyword(s):  
Molecular Dynamics ◽  
Severe Acute Respiratory Syndrome ◽  
Angiotensin Converting Enzyme ◽  
Computational Analysis ◽  
Spike Protein ◽  
Short Peptides ◽  
Receptor Binding Domain ◽  
Converting Enzyme ◽  
Angiotensin Converting Enzyme 2 ◽  
Dynamics Simulations

ABSTRACTThe severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of the COVID-19, is spreading globally and has infected more than 3 million people. It has been discovered that SARS-CoV-2 initiates the entry into cells by binding to human angiotensin-converting enzyme 2 (hACE2) through the receptor binding domain (RBD) of its spike glycoprotein. Hence, drugs that can interfere the SARS-CoV-2-RBD binding to hACE2 potentially can inhibit SARS-CoV-2 from entering human cells. Here, based on the N-terminal helix α1 of human ACE2, we designed nine short peptides that have potential to inhibit SARS-CoV-2 binding. Molecular dynamics simulations of peptides in the their free and SARS-CoV-2 RBD-bound forms allow us to identify fragments that are stable in water and have strong binding affinity to the SARS-CoV-2 spike proteins. The important interactions between peptides and RBD are highlighted to provide guidance for the design of peptidomimetics against the SARS-CoV-2.

scholarly journals How does temperature affect the dynamics of SARS-CoV-2 M proteins? Insights from Molecular Dynamics Simulations

2021 ◽  
Author(s):  
Soumya Lipsa Rath ◽  
Madhusmita Tripathy ◽  
Nabanita Mandal
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Membrane Lipids ◽  
Membrane System ◽  
Host Cells ◽  
Coarse Grained ◽  
M Protein ◽  
Effect Of Temperature ◽  
M Proteins ◽  
Dynamics Simulations

Enveloped viruses, in general, have several transmembrane proteins and glycoproteins, which assist the virus in entry and attachment onto the host cells. These proteins also play a significant role in determining the shape and size of the newly formed virus particles. The lipid membrane and the embedded proteins affect each other in non-trivial ways during the course of the viral life cycle. Unravelling the nature of the protein-protein and protein-lipid interactions, under various environmental and physiological conditions, could therefore prove to be crucial in development of therapeutics. Here, we study the M protein of SARS-CoV-2 to understand the effect of temperature on the properties of the protein-membrane system. The membrane embedded dimeric M proteins were studied using atomistic and coarse-grained molecular dynamics simulations at temperatures ranging between 10 and 50 ˚C. While temperature induced fluctuations should be monotonic, we observe a steady rise in the protein dynamics up to 40 ˚C, beyond which it surprisingly reverts back to the low temperature behaviour. Detailed investigation reveals disordering of the membrane lipids in the presence of the protein, which induces additional curvature around the transmembrane region. Coarse-grained simulations indicate temperature dependent aggregation of M protein dimers. Our study clearly indicates that the dynamics of membrane lipids and integral M protein of SARS-CoV-2 enables it to better associate and aggregate only at a certain temperature range (i.e., ~30 to 40 ˚C). This can have important implications in the protein aggregation and subsequent viral budding/fission processes.   

scholarly journals Computational design of ACE2-based short peptide inhibitors of SARS-CoV-2

2020 ◽  
Author(s):  
Yanxiao Han ◽  
Petr Kral
Keyword(s):  
Molecular Dynamics ◽  
Computational Design ◽  
Peptide Inhibitors ◽  
Converting Enzyme ◽  
Protease Domain ◽  
Alpha Helices ◽  
Angiotensin Converting Enzyme 2 ◽  
Short Peptide ◽  
Binding Domains ◽  
Dynamics Simulations

<div>Peptide inhibitors against the SARS-CoV-2 coronavirus, currently causing a worldwide pandemic, are designed and simulated. The inhibitors are formed by two sequential self-supporting alpha-helices (bundle) extracted from the protease domain (PD) of angiotensin-converting enzyme 2 (ACE2), which binds to the SARS-CoV-2 receptor binding domains. Molecular dynamics simulations revealed that the peptides maintain their secondary structure and provide a highly specific and stable binding (blocking) to SARS-CoV-2, determined by their sequences and conformations. The proposed peptide inhibitors could provide simple therapeutics against the COVID-19 disease.</div>

scholarly journals Structure-guided glyco-engineering of ACE2 for improved potency as soluble SARS-CoV-2 decoy receptor

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Tümay Capraz ◽  
Nikolaus Ferdinand Kienzl ◽  
Elisabeth Laurent ◽  
Jan W Perthold ◽  
Esther Föderl-Höbenreich ◽  
...  
Keyword(s):  
Viral Entry ◽  
Structural Models ◽  
Site Directed Mutagenesis ◽  
Host Cells ◽  
Directed Mutagenesis ◽  
Binding Affinities ◽  
Clinical Tests ◽  
Angiotensin Converting Enzyme 2 ◽  
Decoy Receptor ◽  
Dynamics Simulations

Infection and viral entry of SARS-CoV-2 crucially depends on the binding of its Spike protein to angiotensin converting enzyme 2 (ACE2) presented on host cells. Glycosylation of both proteins is critical for this interaction. Recombinant soluble human ACE2 can neutralize SARS-CoV-2 and is currently undergoing clinical tests for the treatment of COVID-19. We used 3D structural models and molecular dynamics simulations to define the ACE2 N-glycans that critically influence Spike-ACE2 complex formation. Engineering of ACE2 N-glycosylation by site-directed mutagenesis or glycosidase treatment resulted in enhanced binding affinities and improved virus neutralization without notable deleterious effects on the structural stability and catalytic activity of the protein. Importantly, simultaneous removal of all accessible N-glycans from recombinant soluble human ACE2 yields a superior SARS-CoV-2 decoy receptor with promise as effective treatment for COVID-19 patients.

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

2022 ◽  
Author(s):  
Liping Zhou ◽  
Leyun Wu ◽  
Cheng Peng ◽  
Yanqing Yang ◽  
Yulong Shi ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Severe Acute Respiratory Syndrome ◽  
Molecular Dynamics Simulations ◽  
Immune Escape ◽  
Spike Protein ◽  
Dynamics Simulations

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)...

scholarly journals Genetic variability in the expression of the SARS-CoV-2 host cell entry factors across populations

2020 ◽  
Author(s):  
Lourdes Ortiz-Fernández ◽  
Amr H Sawalha
Keyword(s):  
Host Cell ◽  
Viral Entry ◽  
Quantitative Measure ◽  
Individual Variability ◽  
Host Cells ◽  
Genetic Determinants ◽  
Angiotensin Converting Enzyme 2 ◽  
African Populations ◽  
Host Cell Entry ◽  
Host Cell Membranes

AbstractThe entry of SARS-CoV-2 into host cells is dependent upon angiotensin-converting enzyme 2 (ACE2), which serves as a functional attachment receptor for the viral spike glycoprotein, and the serine protease TMPRSS2 which allows fusion of the viral and host cell membranes. We devised a quantitative measure to estimate genetic determinants of ACE2 and TMPRSS2 expression and applied this measure to >2,500 individuals. Our data show significant variability in genetic determinants of ACE2 and TMPRSS2 expression among individuals and between populations, and demonstrate a genetic predisposition for lower expression levels of both key viral entry genes in African populations. These data suggest that genetic factors might lead to lower susceptibility for SARS-CoV-2 infection in African populations and that host genetics might help explain inter-individual variability in disease susceptibility and severity of COVID-19.

scholarly journals Millisecond-scale molecular dynamics simulation of spike RBD structure reveals evolutionary adaption of SARS-CoV-2 to stably bind ACE2

2020 ◽  
Author(s):  
Gard Nelson ◽  
Oleksandr Buzko ◽  
Aaron Bassett ◽  
Patricia R Spilman ◽  
Kayvan Niazi ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Md Simulations ◽  
Host Cells ◽  
Dynamics Simulation ◽  
Receptor Binding Domain ◽  
Binding Region ◽  
Angiotensin Converting Enzyme 2 ◽  
Molecular Binding ◽  
Relative Affinity ◽  
Therapeutic Development

The Receptor Binding Domain (RBD) of the SARS-CoV-2 surface spike (S) protein interacts with host angiotensin converting enzyme 2 (ACE2) to gain entry to host cells and initiate infection 1-3. Detailed, accurate understanding of key interactions between S RBD and ACE2 provides critical information that may be leveraged in the development of strategies for the prevention and treatment of COVID-19. Utilizing the published sequences and cryo-EM structures of both the viral S RBD and ACE2 4,5, we performed in silico molecular dynamics (MD) simulations of free S RBD and of its interaction with ACE2 over the exceptionally long durations of 2.9 and 2 milliseconds, respectively, to elucidate the nature and relative affinity of S RBD surface residues for the ACE2 binding region. Our findings reveal that free S RBD has assumed an optimized ACE2 binding-ready conformation, incurring little entropic penalty for binding, an evolutionary adaptation that contributes to its high affinity for the receptor 6. We further identified high probability molecular binding interactions that inform both vaccine design and therapeutic development, which may include recombinant ACE2-based spike decoys 7 and/or allosteric S RBD-ACE2 binding inhibitors 8,9 to prevent or arrest infection and thus disease.

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