scholarly journals Analysis of the mutation dynamics of SARS-CoV-2 reveals the spread history and emergence of RBD mutant with lower ACE2 binding affinity

2020 ◽  
Author(s):  
Yong Jia ◽  
Gangxu Shen ◽  
Yujuan Zhang ◽  
Keng-Shiang Huang ◽  
Hsing-Ying Ho ◽  
...  
Keyword(s):  
Binding Affinity ◽  
Mutation Rate ◽  
Receptor Binding ◽  
Vaccine Development ◽  
Early Stage ◽  
Minimum Evolution ◽  
S Protein ◽  
Phylogeny Analysis ◽  
Protein Encoding ◽  
Mutation Dynamics

SummaryMonitoring the mutation dynamics of SARS-CoV-2 is critical for the development of effective approaches to contain the pathogen. By analyzing 106 SARS-CoV-2 and 39 SARS genome sequences, we provided direct genetic evidence that SARS-CoV-2 has a much lower mutation rate than SARS. Minimum Evolution phylogeny analysis revealed the putative original status of SARS-CoV-2 and the early-stage spread history. The discrepant phylogenies for the spike protein and its receptor binding domain proved a previously reported structural rearrangement prior to the emergence of SARS-CoV-2. Despite that we found the spike glycoprotein of SARS-CoV-2 is particularly more conserved, we identified a mutation that leads to weaker receptor binding capability, which concerns a SARS-CoV-2 sample collected on 27th January 2020 from India. This represents the first report of a significant SARS-CoV-2 mutant, and raises the alarm that the ongoing vaccine development may become futile in future epidemic if more mutations were identified.HighlightsBased on the currently available genome sequence data, we proved that SARS-COV-2 genome has a much lower mutation rate and genetic diversity than SARS during the 2002-2003 outbreak.The spike (S) protein encoding gene of SARS-COV-2 is found relatively more conserved than other protein-encoding genes, which is a good indication for the ongoing antiviral drug and vaccine development.Minimum Evolution phylogeny analysis revealed the putative original status of SARS-CoV-2 and the early-stage spread history.We confirmed a previously reported rearrangement in the S protein arrangement of SARS-COV-2, and propose that this rearrangement should have occurred between human SARS-CoV and a bat SARS-CoV, at a time point much earlier before SARS-COV-2 transmission to human.We provided first evidence that a mutated SARS-COV-2 with reduced human ACE2 receptor binding affinity have emerged in India based on a sample collected on 27th January 2020.

scholarly journals Fast assessment of human receptor-binding capability of 2019 novel coronavirus (2019-nCoV)

2020 ◽  
Author(s):  
Qiang Huang ◽  
Andreas Herrmann
Keyword(s):  
Binding Affinity ◽  
Receptor Binding ◽  
Large Scale ◽  
Quantitative Methods ◽  
Complex Structure ◽  
Protein Docking ◽  
Monte Carlo Algorithm ◽  
S Protein ◽  
Transmission Capability ◽  
Human Receptor

AbstractThe outbreaks of 2002/2003 SARS, 2012/2015 MERS and 2019/2020 Wuhan respiratory syndrome clearly indicate that genome evolution of an animal coronavirus (CoV) may enable it to acquire human transmission ability, and thereby to cause serious threats to global public health. It is widely accepted that CoV human transmission is driven by the interactions of its spike protein (S-protein) with human receptor on host cell surface; so, quantitative evaluation of these interactions may be used to assess the human transmission capability of CoVs. However, quantitative methods directly using viral genome data are still lacking. Here, we perform large-scale protein-protein docking to quantify the interactions of 2019-nCoV S-protein receptor-binding domain (S-RBD) with human receptor ACE2, based on experimental SARS-CoV S-RBD-ACE2 complex structure. By sampling a large number of thermodynamically probable binding conformations with Monte Carlo algorithm, this approach successfully identified the experimental complex structure as the lowest-energy receptor-binding conformations, and hence established an experiment-based strength reference for evaluating the receptor-binding affinity of 2019-nCoV via comparison with SARS-CoV. Our results show that this binding affinity is about 73% of that of SARS-CoV, supporting that 2019-nCoV may cause human transmission similar to that of SARS-CoV. Thus, this study presents a method for rapidly assessing the human transmission capability of a newly emerged CoV and its mutant strains, and demonstrates that post-genome analysis of protein-protein interactions may provide early scientific guidance for viral prevention and control.

Structure, Dynamics, Receptor Binding, and Antibody Binding of Fully-glycosylated Full-length SARS-CoV-2 Spike Protein in a Viral Membrane

2020 ◽  
Author(s):  
Yeol Kyo Choi ◽  
Yiwei Cao ◽  
Martin Frank ◽  
Hyeonuk Woo ◽  
Sang-Jun Park ◽  
...  
Keyword(s):  
Receptor Binding ◽  
Vaccine Development ◽  
Accessible Surface Area ◽  
Full Length ◽  
S Protein ◽  
Viral Membrane ◽  
Accessible Surface ◽  
Dynamics Simulations ◽  
The Impact ◽  
Insight Into

ABSTRACTThe spike (S) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mediates host cell entry by binding to angiotensin-converting enzyme 2 (ACE2), and is considered the major target for drug and vaccine development. We previously built fully-glycosylated full-length SARS-CoV-2 S protein models in a viral membrane including both open and closed conformations of receptor binding domain (RBD) and different templates for the stalk region. In this work, multiple μs-long all-atom molecular dynamics simulations were performed to provide deeper insight into the structure and dynamics of S protein, and glycan functions. Our simulations reveal that the highly flexible stalk is composed of two independent joints and most probable S protein orientations are competent for ACE2 binding. We identify multiple glycans stabilizing the open and/or closed states of RBD, and demonstrate that the exposure of antibody epitopes can be captured by detailed antibody-glycan clash analysis instead of a commonly-used accessible surface area analysis that tends to overestimate the impact of glycan shielding and neglect possible detailed interactions between glycan and antibody. Overall, our observations offer structural and dynamic insight into SARS-CoV-2 S protein and potentialize for guiding the design of effective antiviral therapeutics.

scholarly journals Structural remodeling of SARS-CoV-2 spike protein glycans reveals the regulatory roles in receptor binding affinity

2021 ◽  
Author(s):  
Yen-Pang Hsu ◽  
Debopreeti Mukherjee ◽  
Vladimir Shchurik ◽  
Alexey Makarov ◽  
Benjamin F. Mann
Keyword(s):  
Binding Affinity ◽  
Receptor Binding ◽  
Binding Domain ◽  
Spike Protein ◽  
Receptor Binding Domain ◽  
S Protein ◽  
Receptor Binding Affinity ◽  
Protein Receptor ◽  
Regulatory Effects

AbstractGlycans of the SARS-CoV-2 spike protein are speculated to play functional roles in the infection processes as they extensively cover the protein surface and are highly conserved across the variants. To date, the spike protein has become the principal target for vaccine and therapeutic development while the exact effects of its glycosylation remain elusive. Experimental reports have described the heterogeneity of the spike protein glycosylation profile. Subsequent molecular simulation studies provided a knowledge basis of the glycan functions. However, there are no studies to date on the role of discrete glycoforms on the spike protein pathobiology. Building an understanding of its role in SARS-CoV-2 is important as we continue to develop effective medicines and vaccines to combat the disease. Herein, we used designed combinations of glycoengineering enzymes to simplify and control the glycosylation profile of the spike protein receptor-binding domain (RBD). Measurements of the receptor binding affinity revealed the regulatory effects of the RBD glycans. Remarkably, opposite effects were observed from differently remodeled glycans, which presents a potential strategy for modulating the spike protein behaviors through glycoengineering. Moreover, we found that the reported anti-SARS-CoV-(2) antibody, S309, neutralizes the impact of different RBD glycoforms on the receptor binding affinity. Overall, this work reports the regulatory roles that glycosylation plays in the interaction between the viral spike protein and host receptor, providing new insights into the nature of SARS-CoV-2. Beyond this study, enzymatic remodeling of glycosylation offers the opportunity to understand the fundamental role of specific glycoforms on glycoconjugates across molecular biology.Covert art LegendsThe glycosylation of the SARS-CoV-2 spike protein receptor-binding domain has regulatory effects on the receptor binding affinity. Sialylation or not determines the “stabilizing” or “destabilizing” effect of the glycans. (Protein structure model is adapted from Protein Data Bank: 6moj. The original model does not contain the glycan structure.)SignificanceGlycans extensively cover the surface of SARS-CoV-2 spike (S) protein but the relationships between the glycan structures and the protein pathological behaviors remain elusive. Herein, we simplified and harmonized the glycan structures in the S protein receptor-binding domain and reported their regulatory roles in human receptor interaction. Opposite regulatory effects were observed and were determined by discrete glycan structures, which can be neutralized by the reported S309 antibody binding to the S protein. This report provides new insight into the mechanism of SARS-CoV-2 S protein infection as well as S309 neutralization.

scholarly journals Epidemiological and Genomic Analysis of SARS-CoV-2 in Ten Patients from a Mid-sized City outside of Hubei, China

2020 ◽  
Author(s):  
Jinkun Chen ◽  
Evann E. Hilt ◽  
Huan Wu ◽  
Zhuojing Jiang ◽  
QinChao Zhang ◽  
...  
Keyword(s):  
Mutation Rate ◽  
Nucleotide Substitution ◽  
Vaccine Development ◽  
Early Stage ◽  
Genomic Analysis ◽  
Dynamic Nature ◽  
Travel History ◽  
Viral Genomes ◽  
Living Together ◽  
Novel Coronavirus

ABSTRACTA novel coronavirus known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of the ongoing COVID-19 pandemic. In this study, we performed a comprehensive epidemiological and genomic analysis of SARS-CoV-2 genomes from ten patients in Shaoxing, a mid-sized city outside of the epicenter Hubei province, China, during the early stage of the outbreak (late January to early February, 2020). We obtained viral genomes with > 99% coverage and a mean depth of 296X demonstrating that viral genomic analysis is feasible via metagenomics sequencing directly on nasopharyngeal samples with SARS-CoV-2 Real-time PCR Ct values less than 28. We found that a cluster of 4 patients with travel history to Hubei shared the exact same virus with patients from Wuhan, Taiwan, Belgium and Australia, highlighting how quickly this virus spread to the globe. The virus from another cluster of two family members living together without travel history but with a sick contact of a confirmed case from another city outside of Hubei accumulated significantly more mutations (9 SNPs vs average 4 SNPs), suggesting a complex and dynamic nature of this outbreak. We also found 70% patients in this study had the S genotype, consistent with an early study showing a higher prevalence of genotype out of Hubei than that inside Hubei. We calculated an average mutation rate of 1.37×10−3 nucleotide substitution per site per year, which is similar to that of other coronaviruses. Our findings add to the growing knowledge of the epidemiological and genomic characteristics of SARS-CoV-2 that are important for guiding outbreak containment and vaccine development. The moderate mutation rate of this virus also lends hope that development of an effective, long-lasting vaccine may be possible.

scholarly journals Cold sensitivity of the SARS-CoV-2 spike ectodomain

2020 ◽  
Author(s):  
Robert J Edwards ◽  
Katayoun Mansouri ◽  
Victoria Stalls ◽  
Kartik Manne ◽  
Brian Watts ◽  
...  
Keyword(s):  
Receptor Binding ◽  
Vaccine Development ◽  
Protein A ◽  
Binding Domain ◽  
Cold Temperature ◽  
Cold Sensitivity ◽  
Receptor Binding Domain ◽  
Primary Target ◽  
S Protein

AbstractThe SARS-CoV-2 spike (S) protein, a primary target for COVID-19 vaccine development, presents its Receptor Binding Domain in two conformations: receptor-accessible “up” or receptor-inaccessible “down” conformations. Here, we report that the commonly used stabilized S ectodomain construct “2P” is sensitive to cold temperature, and that this cold sensitivity is resolved in a “down” state stabilized spike. Our results will impact structural, functional and vaccine studies that use the SARS-CoV-2 S ectodomain.

scholarly journals The Inherent Flexibility of Receptor Binding Domains in SARS-CoV-2 Spike Protein

2021 ◽  
Author(s):  
Hisham M. Dokainish ◽  
Suyong Re ◽  
Takaharu Mori ◽  
Chigusa Kobayashi ◽  
Jaewoon Jung ◽  
...  
Keyword(s):  
Receptor Binding ◽  
Conformational Changes ◽  
Neutralizing Antibodies ◽  
Rational Design ◽  
Vaccine Development ◽  
Antiviral Drug ◽  
Salt Bridges ◽  
Virus Surface ◽  
Structure Transition ◽  
S Protein

Spike (S) protein is the primary antigenic target for neutralization and vaccine development for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It decorates the virus surface and undergoes large conformational changes of its receptor binding domain (RBD) to enter the host cell, as the abundant structural studies suggest. Here, we observe Down, one-Up, one-Open, and two-Up-like structures in enhanced molecular dynamics simulations without pre-defined reaction coordinates. The RBDA transition from Down to one-Up is supported by transient salt-bridges between RBDA and RBDC and by the glycan at N343B. Reduced interactions between RBDA and RBDB induce the RBDB motions toward two-Up. Glycan shielding for neutralizing antibodies is the weakest in one-Open. Cryptic pockets are revealed at the RBD interfaces in intermediate structures between Down and one-Up. The inherent flexibility in S-protein is, thus, essential for the structure transition and shall be considered for antiviral drug rational design or vaccine development.

scholarly journals Catechin and curcumin interact with S protein of SARS-CoV2 and ACE2 of human cell membrane: insights from computational studies

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Atala B. Jena ◽  
Namrata Kanungo ◽  
Vinayak Nayak ◽  
G. B. N. Chainy ◽  
Jagneshwar Dandapat
Keyword(s):  
Amino Acid ◽  
Binding Affinity ◽  
Receptor Binding ◽  
Computational Study ◽  
Cell Receptor ◽  
Binding Domain ◽  
Spike Protein ◽  
Receptor Binding Domain ◽  
Amino Acid Residues ◽  
S Protein

AbstractThe recent outbreak of the coronavirus (SARS-CoV2) is an unprecedented threat to human health and society across the globe. In this context, development of suitable interventions is the need of the hour. The viral spike protein (S Protein) and the cognate host cell receptor ACE2 can be considered as effective and appropriate targets for interventions. It is evident from the present computational study, that catechin and curcumin, not only exhibit strong binding affinity to viral S Protein and host receptor ACE2 but also to their complex (receptor-binding domain (RBD) of the spike protein of SARS-CoV2 and ACE2; RBD/ACE2-complex). The binding affinity values of catechin and curcumin for the S protein, ACE2 and RBD/ACE2-complex are − 10.5 and − 7.9 kcal/mol; − 8.9 and − 7.8 kcal/mol; and − 9.1 and − 7.6 kcal/mol, respectively. Curcumin directly binds to the receptor binding domain (RBD) of viral S Protein. Molecular simulation study over a period of 100 ns further substantiates that such interaction within RBD site of S Protein occurs during 40–100 ns out of 100 ns simulation trajectory. Contrary to this, catechin binds with amino acid residues present near the RBD site of S Protein and causes fluctuation in the amino acid residues of the RBD and its near proximity. Both catechin and curcumin bind the interface of ‘RBD/ACE2-complex’ and intervene in causing fluctuation of the alpha helices and beta-strands of the protein complex. Protein–protein interaction studies in presence of curcumin or catechin also corroborate the above findings suggesting the efficacy of these two polyphenols in hindering the formation of S Protein-ACE2 complex. In conclusion, this computational study for the first time predicts the possibility of above two polyphenols for therapeutic strategy against SARS-CoV2.

Antiproliferative and antiviral effects of mutated IFN-alpha with increased IFN receptor binding affinity

2011 ◽  
Vol 49 (01) ◽  
Author(s):  
MF Sprinzl ◽  
L Bührer ◽  
D Strand ◽  
G Schreiber ◽  
PR Galle ◽  
...  
Keyword(s):  
Binding Affinity ◽  
Receptor Binding ◽  
Receptor Binding Affinity ◽  
Ifn Alpha ◽  
Antiviral Effects
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