scholarly journals The N501Y and K417N mutations in the spike protein of SARS-CoV-2 alter the interactions with both hACE2 and human derived antibody: A Free energy of perturbation study

2020 ◽  
Author(s):  
Filip Fratev
Keyword(s):  
South Africa ◽  
Immune Response ◽  
Free Energy ◽  
Molecular Level ◽  
Spike Protein ◽  
Free Energy Perturbation ◽  
Receptor Binding Domain ◽  
Human Immune Response ◽  
Human Immune ◽  
Energy Perturbation

AbstractThe N501Y and K417N mutations in spike protein of SARS-CoV-2 and their combination arise questions but the data about their mechanism of action at molecular level is limited. Here, we present Free energy perturbation (FEP) calculations for the interactions of the spike S1 receptor binding domain (RBD) with both the ACE2 receptor and an antibody derived from COVID-19 patients. Our results shown that the S1 RBD-ACE2 interactions were significantly increased whereas those with the STE90-C11 antibody dramatically decreased; about over 100 times. The K417N mutation had much more pronounced effect and in a combination with N501Y fully abolished the antibody effect. This may explain the observed in UK and South Africa more spread of the virus but also raise an important question about the possible human immune response and the success of already available vaccines.

scholarly journals Prediction and evolution of the molecular fitness of SARS-CoV-2 variants: Introducing SpikePro

2021 ◽  
Author(s):  
Fabrizio Pucci ◽  
Marianne Rooman
Keyword(s):  
Immune Response ◽  
Neutralizing Antibodies ◽  
Molecular Mechanisms ◽  
Population Level ◽  
Critical Issue ◽  
Spike Protein ◽  
Human Immune Response ◽  
Human Immune ◽  
The Stability ◽  
The Impact

The understanding of the molecular mechanisms driving the fitness of the SARS-CoV-2 virus and its mutational evolution is still a critical issue. We built a simplified computational model, called SpikePro, to predict the SARS-CoV-2 fitness from the amino acid sequence and structure of the spike protein. It contains three contributions: the viral transmissibility predicted from the stability of the spike protein, the infectivity computed in terms of the affinity of the spike protein for the ACE2 receptor, and the ability of the virus to escape from the human immune response based on the binding affinity of the spike protein for a set of neutralizing antibodies. Our model reproduces well the available experimental, epidemiological and clinical data on the impact of variants on the biophysical characteristics of the virus. For example, it is able to identify circulating viral strains that, by increasing their fitness, recently became dominant at the population level. SpikePro is a useful instrument for the genomic surveillance of the SARS-CoV-2 virus, since it predicts in a fast and accurate way the emergence of new viral strains and their dangerousness. It is freely available in the GitHub repository github.com/3BioCompBio/SpikeProSARS-CoV-2.

scholarly journals The High Transmission of SARS-CoV-2 Omicron (B.1.1.529) Variant is Not Only Due to Its hACE2 binding: A Free Energy of Perturbation Study

2021 ◽  
Author(s):  
Filip Fratev
Keyword(s):  
South Africa ◽  
Free Energy ◽  
Molecular Level ◽  
Binding Capacity ◽  
Spike Protein ◽  
Structural Basis ◽  
New Variant ◽  
Alpha Variant ◽  
Special Circumstances ◽  
Interaction Surface

AbstractThe mutations in the spike protein of SARS-CoV-2 Omicron variant (B.1.1.529 lineage) gave rise to questions, but the data on the mechanism of action at the molecular level is limited. In this study, we present the Free energy of perturbation (FEP) data about the RBD-hACE2 binding of this new variant.We identified two groups of mutations located close to the most contributing substitutions Q498R and Q493R, which altered significantly the RBD-hACE2 interactions. The Q498R, Y505H and G496S mutations, in addition to N501Y, highly increased the binding to hACE2. They enhanced the binding by 98, 14 and 13 folds, respectively, which transforms the S1-RBD to a picomolar binder. However, in contrast to the case in mice the Q493R/K mutations, in a combination with K417N and T478K, dramatically reduced the S1 RBD binding by over 100 folds. The N440K, G446S and T478K substitutions had lesser contribution. Thus, the total effect of these nine mutations located on the interaction surface of RBD-hACE2 turns out to be similar to that observed in the Alpha variant. In a special circumstances it could be further altered by the E484A and S477N mutations and even lower binding capacity is likely to be detected. Finally, we provide a structural basis of the observed changes in the interactions.These data may explain only partially the observed in South Africa extremely high Omicron spread and is in support to the hypothesis for multiple mechanisms of actions involved in the transmission.Graphical abstract

scholarly journals Critical interactions for SARS-CoV-2 spike protein binding to ACE2 identified by machine learning

2021 ◽  
Author(s):  
Anna Pavlova ◽  
Zijian Zhang ◽  
Atanu Acharya ◽  
Diane L. Lynch ◽  
Yui Tik Pang ◽  
...  
Keyword(s):  
Machine Learning ◽  
Experimental Studies ◽  
Md Simulations ◽  
Spike Protein ◽  
Free Energy Perturbation ◽  
Receptor Binding Domain ◽  
Free Energies ◽  
Energy Perturbation ◽  
The Individual ◽  
Binding Free Energies

ABSTRACTBoth SARS-CoV and SARS-CoV-2 bind to the human ACE2 receptor. Based on high-resolution structures, the two viruses bind in practically identical conformations, although several residues of the receptor-binding domain (RBD) differ between them. Here we have used molecular dynamics (MD) simulations, machine learning (ML), and free energy perturbation (FEP) calculations to elucidate the differences in RBD binding by the two viruses. Although only subtle differences were observed from the initial MD simulations of the two RBD-ACE2 complexes, ML identified the individual residues with the most distinctive ACE2 interactions, many of which have been highlighted in previous experimental studies. FEP calculations quantified the corresponding differences in binding free energies to ACE2, and examination of MD trajectories provided structural explanations for these differences. Lastly, the energetics of emerging SARS-CoV-2 mutations were studied, showing that the affinity of the RBD for ACE2 is increased by N501Y and E484K mutations but is slightly decreased by K417N.

scholarly journals Free energy perturbation calculations on binding and catalysis after mutating threonine 220 in subtilisin

1991 ◽  
Vol 266 (18) ◽  
pp. 11801-11809
Author(s):  
N. Mizushima ◽  
D. Spellmeyer ◽  
S. Hirono ◽  
D. Pearlman ◽  
P. Kollman
Keyword(s):  
Free Energy ◽  
Free Energy Perturbation ◽  
Energy Perturbation

scholarly journals Assessing the human immune response to SARS-CoV-2 variants

2021 ◽  
Vol 27 (4) ◽  
pp. 571-572 ◽  
Author(s):  
Roberto Burioni ◽  
Eric J. Topol
Keyword(s):  
Immune Response ◽  
Human Immune Response ◽  
Human Immune

scholarly journals Potent Noncovalent Inhibitors of the Main Protease of SARS-CoV-2 from Molecular Sculpting of the Drug Perampanel Guided by Free Energy Perturbation Calculations

2021 ◽  
Vol 7 (3) ◽  
pp. 467-475 ◽  
Author(s):  
Chun-Hui Zhang ◽  
Elizabeth A. Stone ◽  
Maya Deshmukh ◽  
Joseph A. Ippolito ◽  
Mohammad M. Ghahremanpour ◽  
...  
Keyword(s):  
Free Energy ◽  
Free Energy Perturbation ◽  
Main Protease ◽  
Energy Perturbation

scholarly journals Approaches to Modelling the Human Immune Response in Transition of Candidates from Research to Development

2014 ◽  
Vol 2014 ◽  
pp. 1-6 ◽  
Author(s):  
Diane Williamson
Keyword(s):  
Immune Response ◽  
Human Immune Response ◽  
Human Immune ◽  
Animal Rule

This review considers the steps required to evaluate a candidate biodefense vaccine or therapy as it emerges from the research phase, in order to transition it to development. The options for preclinical modelling of efficacy are considered in the context of the FDA’s Animal Rule.

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