In silico analysis of SARS-CoV-2 spike glycoprotein and insights into antibody binding (original) (raw)
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In silico Antibody Mutagenesis for Optimizing its Binding to the Spike Protein of SARS-CoV-2
2020
Coronavirus disease 2019 (COVID-19) is an ongoing global pandemic and there are currently no FDA approved medicines for treatment or prevention. Inspired by promising outcomes for convalescent plasma treatment, developing antibody drugs (biologics) to block SARS-CoV-2 infection has been the focus of drug discovery, along with tremendous efforts in repurposing small-molecule drugs. In the last several months, experimentally, many human neutralizing monoclonal antibodies (mAbs) were successfully extracted from plasma of recovered COVID-19 patients. Currently, several mAbs targeting the SARS-CoV-2's spike protein (Spro) are in clinical trials. With known atomic structures of mAb-Spro complex, it becomes possible to in silico investigate the molecular mechanism of mAb's binding with Spro and design more potent mAbs through protein mutagenesis studies, complementary to existing experimental efforts. Leveraging superb computing power nowadays, we propose a fully automated in silic...
2020
Neutralizing monoclonal antibodies (nAbs) to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) represent promising candidates for clinical intervention against coronavirus virus diseases 2019 (COVID-19). We isolated a large number of nAbs from SARS-CoV-2 infected individuals capable of disrupting proper interaction between the receptor binding domain (RBD) of the viral spike (S) protein and the receptor angiotensin converting enzyme 2 (ACE2). In order to understand the mechanism of these nAbs on neutralizing SARS-CoV-2 virus infections, we have performed cryo-EM analysis and here report cryo-EM structures of the ten most potent nAbs in their native full-length IgG or Fab forms bound to the trimeric S protein of SARS-CoV-2. The bivalent binding of the full-length IgG is found to associate with more RBD in the “up” conformation than the monovalent binding of Fab, perhaps contributing to the enhanced neutralizing activity of IgG and triggering more shedding of the S1 subunit...
Viruses
Currently, SARS-CoV-2 causing coronavirus disease 2019 (COVID-19) is responsible for one of the most deleterious pandemics of our time. The interaction between the ACE2 receptors at the surface of human cells and the viral Spike (S) protein triggers the infection, making the receptor-binding domain (RBD) of the SARS-CoV-2 S-protein a focal target for the neutralizing antibodies (Abs). Despite the recent progress in the development and deployment of vaccines, the emergence of novel variants of SARS-CoV-2 insensitive to Abs produced in response to the vaccine administration and/or monoclonal ones represent a potential danger. Here, we analyzed the diversity of neutralizing Ab epitopes and assessed the possible effects of single and multiple mutations in the RBD of SARS-CoV-2 S-protein on its binding affinity to various antibodies and the human ACE2 receptor using bioinformatics approaches. The RBD-Ab complexes with experimentally resolved structures were grouped into four clusters wit...
Structures of the SARS-CoV-2 spike glycoprotein and applications for novel drug development
Frontiers in Pharmacology
COVID-19 caused by SARS-CoV-2 has raised a health crisis worldwide. The high morbidity and mortality associated with COVID-19 and the lack of effective drugs or vaccines for SARS-CoV-2 emphasize the urgent need for standard treatment and prophylaxis of COVID-19. The receptor-binding domain (RBD) of the glycosylated spike protein (S protein) is capable of binding to human angiotensin-converting enzyme 2 (hACE2) and initiating membrane fusion and virus entry. Hence, it is rational to inhibit the RBD activity of the S protein by blocking the RBD interaction with hACE2, which makes the glycosylated S protein a potential target for designing and developing antiviral agents. In this study, the molecular features of the S protein of SARS-CoV-2 are highlighted, such as the structures, functions, and interactions of the S protein and ACE2. Additionally, computational tools developed for the treatment of COVID-19 are provided, for example, algorithms, databases, and relevant programs. Finally...
2021
ABSTRACTThe SARS-CoV-2 pandemic highlights the need for a detailed molecular understanding of protective antibody responses. This is underscored by the emergence and spread of SARS-CoV-2 variants, including B.1.1.7, P1, and B.1.351, some of which appear to be less effectively targeted by current monoclonal antibodies and vaccines. Here we report a high resolution and comprehensive map of antibody recognition of the SARS-CoV-2 spike receptor binding domain (RBD), which is the target of most neutralizing antibodies, using computational structural analysis. With a dataset of nonredundant experimentally determined antibody-RBD structures, we classified antibodies by RBD residue binding determinants using unsupervised clustering. We also identified the energetic and conservation features of epitope residues and assessed the capacity of viral variant mutations to disrupt antibody recognition, revealing sets of antibodies predicted to effectively target recently described viral variants. T...
Controlling the SARS-CoV-2 Spike Glycoprotein Conformation
2020
The coronavirus (CoV) viral host cell fusion spike (S) protein is the primary immunogenic target for virus neutralization and the current focus of many vaccine design efforts. The highly flexible S-protein, with its mobile domains, presents a moving target to the immune system. Here, to better understand S-protein mobility, we implemented a structure-based vector analysis of available β-CoV S-protein structures. We found that despite overall similarity in domain organization, different β-CoV strains display distinct S-protein configurations. Based on this analysis, we developed two soluble ectodomain constructs in which the highly immunogenic and mobile receptor binding domain (RBD) is locked in either the all-RBDs ‘down’ position or is induced to display a previously unobserved in SARS-CoV-2 2-RBDs ‘up’ configuration. These results demonstrate that the conformation of the S-protein can be controlled via rational design and provide a framework for the development of engineered coron...
Zenodo (CERN European Organization for Nuclear Research), 2023
INTRODUCTIONS The drug discovery process in pharmaceutical industries relies on structure-based computer-aided drug design (SBCADD). Developing novel interventions with potential interaction with therapeutic targets is of paramount significance. The availability of the 3D structures of target proteins has led the foundation to design target-specific drugs based on structure-based drug design methods (1). Usually, analytical techniques like X-ray crystallography and nuclear paramagnetic resonance (NMR) are employed to construct the 3D dimensional structures of the target proteins. Conventionally, these methods are too expensive and timeconsuming. To confound this problem, homology modeling aims to build the 3D structures of the protein based on the protein sequence similarity for which crystallographic structures are already available in the repository for the different organisms. The notion of an online tool SWISS Model, available to build the 3D structures of drug target proteins, is employed in this study (2-3, 4). The inbuilt computational algorithm in the SWISS Model is used to compare, match and analytically predict the 3D coordinates of amino acid residues with the pre-existing protein structures based on sequence similarity. (2,5-6). The outbreak of novel severe acute respiratory syndrome coronavirus-2 (SARS CoV-2) infection has undergone significant mutation since it originated in Wuhan, Hubei province, China, in December 2019 (7). The explosion of SARS CoV-2 has severe morbidity and mortality levels reported by World Health Organization (WHO) in 2021. The mutation and adaptation to the existing environment have ignited concern about the spread of SARS-CoV-2 (8). Significantly numerous SARS-CoV-2 variants were produced ascribable to various mutations emerging within the RBD of the spike (9-10). Among the SARS CoV-2 variants produced, variants of concern (VOC) were identified to have increased transmissibility and virulence (11). It has also increases the flexibility of the spike proteins to interact with the host receptors (12-13).
2020
SummaryUnderstanding the mechanism of neutralizing antibodies (NAbs) against SARS-CoV-2 is critical for effective vaccines and therapeutics development. We recently reported an exceptionally potent NAb, BD-368-2, and revealed the existence ofVH3-53/VH3-66convergent NAbs in COVID-19. Here we report the 3.5-Å cryo-EM structure of BD-368-2’s Fabs in complex with a mutation-induced prefusion-state-stabilized spike trimer. UnlikeVH3-53/VH3-66NAbs, BD-368-2 fully blocks ACE2 binding by occupying all three receptor-binding domains (RBDs) simultaneously, regardless of their “up” and “down” positions. BD-368-2 also triggers fusogenic-like structural rearrangements of the spike trimer, which could impede viral entry. Moreover, BD-368-2 completely avoids the common epitope ofVH3-53/VH3-66NAbs, evidenced by multiple crystal structures of their Fabs in tripartite complexes with RBD, suggesting a new way of pairing potent NAbs to prevent neutralization escape. Together, these results rationalize ...
Chasing COVID-19 through SARS-CoV-2 spike glycoprotein
VirusDisease, 2020
An ongoing pandemic Coronavirus disease (COVID-19), caused by a newly emerged Coronavirus, SARS-CoV-2 has affected millions of people globally. One of the most crucial structural proteins of SARS-CoV-2 is the Spike glycoprotein (S-glycoprotein), for which the first de novo modelling was envisaged by our group in early 2020, and was superimposed to its predecessor SARS-CoV S-glycoprotein, to determine structural divergence, glycosylation and antigenic variation between SARS-CoV-2 and SARS-CoV. S-glycoprotein is involved in binding with the cellular receptor, membrane fusion, internalization via angiotensin-converting enzyme 2 (ACE2) receptor, and tissue tropism. Upon internalization into the target host cells, the viral genome encodes two precursor polypeptides which get processed into 16 mature nonstructural proteins that play a crucial role in replication and transcription of SARS-CoV-2. Currently S-glycoprotein is one of the most vital targets for vaccine and therapeutics development for COVID-19.