Perturbation of ACE2 Structural Ensembles by SARS-CoV-2 Spike Protein Binding

Abstract We present a microsphere-based flow cytometry assay that quantifies the ability of plasma to inhibit the binding of spike protein to angiotensin-converting enzyme 2. Plasma from 22 patients who had recovered from mild coronavirus disease 2019 (COVID-19) and expressed anti–spike protein trimer immunoglobulin G inhibited angiotensin-converting enzyme 2–spike protein binding to a greater degree than controls. The degree of inhibition was correlated with anti–spike protein immunoglobulin G levels, neutralizing titers in a pseudotyped lentiviral assay, and the presence of fever during illness. This inhibition assay may be broadly useful to quantify the functional antibody response of patients recovered from COVID-19 or vaccine recipients in a cell-free assay system.

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Computational approach for the design of potential spike protein binding natural compounds in SARS- CoV2

10.21203/rs.3.rs-33181/v1 ◽

2020 ◽

Author(s):

Anamika Basu ◽

Anasua Sarkar ◽

Ujjwal Maulik

Keyword(s):

Natural Products ◽

Protein Binding ◽

Binding Site ◽

Transmembrane Protein ◽

Experimental Studies ◽

Cost Effective ◽

Docking Study ◽

Spike Protein ◽

Molecular Docking Study ◽

Novel Coronavirus

Abstract Angiotensin converting enzyme 2 (ACE2) (EC:3.4.17.23) is a transmembrane protein which is considered as receptor for spike protein binding of novel coronavirus (SARS-CoV2). Since no specific medication is available to treat COVID-19, designing of new drug is important and essential. In this regard, in silico method plays an important role as it is rapid, cost effective, compared to the trial and error methods using experimental studies. Natural products are safe and easily available to treat coronavirus effected patients, in the present alarming situation. In this paper five phytochemicals which belong to flavonoid and anthraquinone subclass, selected as small molecules in molecular docking study of spike protein of SARS-CoV2 with its human receptor ACE2 molecule. From the detail analysis of their molecular binding site on spike protein binding site with its receptor, hesperidin, emodin and chrysin are selected as competent natural products from both Indian and Chinese medicinal plants, to treat COVID-19.

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SARS-CoV-2 Receptor and Renin-Angiotensin System Regulation: Impact of Genetics Variants in ACE2 Gene Impact of Genetics Variants in the ACE2 Gene in the Functional Receptor of SARS-CoV-2

Volume 5 - 2020, Issue 9 - September - International Journal of Innovative Science and Research Technology ◽

10.38124/ijisrt20jul268 ◽

2020 ◽

Vol 5 (7) ◽

pp. 489-497

Author(s):

Juliana de Oliveira Cruz ◽

Sandra Mara Bispo Sousa

Keyword(s):

Protein Binding ◽

Genetic Variants ◽

Evolutionary Relationship ◽

Physiological Role ◽

Renin Angiotensin System ◽

Spike Protein ◽

Human Populations ◽

Angiotensin System ◽

Renin Angiotensin ◽

Ace2 Gene

The ACE2 has a physiological role in the regulation of the Renin-Angiotensin System. It is also described your function as a receptor for SARS-CoV-2 and other coronaviruses. Genetic variants in ACE2 are associated with cardiovascular diseases in different human populations and drug response. There is no direct evidence that mutations in ACE2 confer resistance to coronavirus spike protein binding. The evolutionary relationship between spike protein binding and ACE2 is complex. Significant genetic variants are present in ACE2, meanwhile, the evolutionary time of contact of the human ACE2 to the virus is short and, therefore, it did not suffer sufficient selective pressures to offer resistance to viral spike protein binding at the population level. More efforts are needed to identify genetic variants in human ACE2 and other genes, and, consequently, conducting case-control studies to validate these variants and their possible association with infection rates by SARS-CoV-2 and/or clinical outcome.

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Mutations in the Spike Protein of Middle East Respiratory Syndrome Coronavirus Transmitted in Korea Increase Resistance to Antibody-Mediated Neutralization

Journal of Virology ◽

10.1128/jvi.01381-18 ◽

2018 ◽

Vol 93 (2) ◽

Cited By ~ 25

Author(s):

Hannah Kleine-Weber ◽

Mahmoud Tarek Elzayat ◽

Lingshu Wang ◽

Barney S. Graham ◽

Marcel A. Müller ◽

...

Keyword(s):

Middle East ◽

Protein Binding ◽

Receptor Binding ◽

Viral Entry ◽

Middle East Respiratory Syndrome ◽

Spike Protein ◽

Target Cells ◽

S Protein ◽

Hospital Outbreak ◽

The Republic

ABSTRACT Middle East respiratory syndrome coronavirus (MERS-CoV) poses a threat to public health. The virus is endemic in the Middle East but can be transmitted to other countries by travel activity. The introduction of MERS-CoV into the Republic of Korea by an infected traveler resulted in a hospital outbreak of MERS that entailed 186 cases and 38 deaths. The MERS-CoV spike (S) protein binds to the cellular protein DPP4 via its receptor binding domain (RBD) and mediates viral entry into target cells. During the MERS outbreak in Korea, emergence and spread of viral variants that harbored mutations in the RBD, D510G and I529T, was observed. Counterintuitively, these mutations were found to reduce DPP4 binding and viral entry into target cells. In this study, we investigated whether they also exerted proviral effects. We confirm that changes D510G and I529T reduce S protein binding to DPP4 but show that this reduction only translates into diminished viral entry when expression of DPP4 on target cells is low. Neither mutation modulated S protein binding to sialic acids, S protein activation by host cell proteases, or inhibition of S protein-driven entry by interferon-induced transmembrane proteins. In contrast, changes D510G and I529T increased resistance of S protein-driven entry to neutralization by monoclonal antibodies and sera from MERS patients. These findings indicate that MERS-CoV variants with reduced neutralization sensitivity were transmitted during the Korean outbreak and that the responsible mutations were compatible with robust infection of cells expressing high levels of DPP4. IMPORTANCE MERS-CoV has pandemic potential, and it is important to identify mutations in viral proteins that might augment viral spread. In the course of a large hospital outbreak of MERS in the Republic of Korea in 2015, the spread of a viral variant that contained mutations in the viral spike protein was observed. These mutations were found to reduce receptor binding and viral infectivity. However, it remained unclear whether they also exerted proviral effects. We demonstrate that these mutations reduce sensitivity to antibody-mediated neutralization and are compatible with robust infection of target cells expressing large amounts of the viral receptor DPP4.

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SARS-CoV-2 spike-protein D614G mutation increases virion spike density and infectivity

Nature Communications ◽

10.1038/s41467-020-19808-4 ◽

2020 ◽

Vol 11 (1) ◽

Cited By ~ 5

Author(s):

Lizhou Zhang ◽

Cody B. Jackson ◽

Huihui Mou ◽

Amrita Ojha ◽

Haiyong Peng ◽

...

Keyword(s):

Protein Binding ◽

Protein S ◽

Spike Protein ◽

Neutralization Sensitivity ◽

Spike Density ◽

S Protein ◽

Virus Like Particles ◽

Protein Incorporation ◽

S Proteins

AbstractSARS-CoV-2 variants with spike (S)-protein D614G mutations now predominate globally. We therefore compare the properties of the mutated S protein (SG614) with the original (SD614). We report here pseudoviruses carrying SG614 enter ACE2-expressing cells more efficiently than those with SD614. This increased entry correlates with less S1-domain shedding and higher S-protein incorporation into the virion. Similar results are obtained with virus-like particles produced with SARS-CoV-2 M, N, E, and S proteins. However, D614G does not alter S-protein binding to ACE2 or neutralization sensitivity of pseudoviruses. Thus, D614G may increase infectivity by assembling more functional S protein into the virion.

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Comparative Perturbation-Based Modeling of the SARS-CoV-2 Spike Protein Binding with Host Receptor and Neutralizing Antibodies: Structurally Adaptable Allosteric Communication Hotspots Define Spike Sites Targeted by Global Circulating Mutations

Biochemistry ◽

10.1021/acs.biochem.1c00139 ◽

2021 ◽

Author(s):

Gennady M. Verkhivker ◽

Steve Agajanian ◽

Deniz Yazar Oztas ◽

Grace Gupta

Keyword(s):

Protein Binding ◽

Neutralizing Antibodies ◽

Spike Protein ◽

Allosteric Communication

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Machine Learning Reveals the Critical Interactions for SARS-CoV-2 Spike Protein Binding to ACE2

The Journal of Physical Chemistry Letters ◽

10.1021/acs.jpclett.1c01494 ◽

2021 ◽

pp. 5494-5502

Author(s):

Anna Pavlova ◽

Zijian Zhang ◽

Atanu Acharya ◽

Diane L. Lynch ◽

Yui Tik Pang ◽

...

Keyword(s):

Machine Learning ◽

Protein Binding ◽

Spike Protein

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Comparative Study of Drug Analysis via Spike Protein Binding Site Recognition and Vaccine Development of Novel Corona Virus

International Journal for Research in Applied Science and Engineering Technology ◽

10.22214/ijraset.2021.33145 ◽

2021 ◽

Vol 9 (3) ◽

pp. 429-439

Author(s):

Pratik Chatterjee

Keyword(s):

Comparative Study ◽

Protein Binding ◽

Binding Site ◽

Vaccine Development ◽

Drug Analysis ◽

Spike Protein ◽

Protein Binding Site ◽

Corona Virus ◽

Site Recognition

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Molecular simulation of SARS-CoV-2 spike protein binding to pangolin ACE2 or human ACE2 natural variants reveals altered susceptibility to infection

Journal of General Virology ◽

10.1099/jgv.0.001452 ◽

2020 ◽

Vol 101 (9) ◽

pp. 921-924 ◽

Cited By ~ 2

Author(s):

Jingfang Wang ◽

Xintian Xu ◽

Xinbo Zhou ◽

Ping Chen ◽

Huiying Liang ◽

...

Keyword(s):

Free Energy ◽

Protein Binding ◽

Binding Affinity ◽

Binding Free Energy ◽

Virus Transmission ◽

Dynamics Simulation ◽

Spike Protein ◽

Susceptibility To Infection ◽

Natural Variants ◽

Complex Models

We constructed complex models of SARS-CoV-2 spike protein binding to pangolin or human ACE2, the receptor for virus transmission, and estimated the binding free energy changes using molecular dynamics simulation. SARS-CoV-2 can bind to both pangolin and human ACE2, but has a significantly lower binding affinity for pangolin ACE2 due to the increased binding free energy (9.5 kcal mol−1). Human ACE2 is among the most polymorphous genes, for which we identified 317 missense single-nucleotide variations (SNVs) from the dbSNP database. Three SNVs, E329G (rs143936283), M82I (rs267606406) and K26R (rs4646116), had a significant reduction in binding free energy, which indicated higher binding affinity than wild-type ACE2 and greater susceptibility to SARS-CoV-2 infection for people with them. Three other SNVs, D355N (rs961360700), E37K (rs146676783) and I21T (rs1244687367), had a significant increase in binding free energy, which indicated lower binding affinity and reduced susceptibility to SARS-CoV-2 infection.

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