The effect of the multiple mutations in Omicron RBD on its binding to human ACE2 receptor and immune evasion: an investigation of molecular dynamics simulations

SARS-coronavirus-2 (SARS-CoV2) Omicron variant (B.1.1.529) is of great concern to the world due to multiple mutations that may have an impact on transmissibility and immune evasion. Compared to the wild type (WT), there are 15 mutations in the Omicron receptor-binding domain (RBD), 10 of which are in the receptor-binding motif (RBM), where the host angiotensin-converting enzyme 2 (ACE2) interacts directly with. As a comparison, the currently dominant variant Delta (B.1.617.2) only has 2 mutations (L452R and T478K) or an additional E484K mutation in the RBM. As many as 15 mutations in Omicron RBD make it very hard to predict whether the mutations would increase the binding affinity to ACE2, particularly considering that 10 mutations crowded in the RBM. To understand the combinatorial mutation effect on Omicron RBD binding to ACE2 and potential immune evasion, we calculated the binding affinities of the WT/Delta/Omicron RBDs to ACE2 and antibodies with 600 ns molecular dynamics simulations for each system. We found that Omicron RBD has slightly weaker ACE2 affinities than WT RBD (-29.39 ± 2.96 Kcal/mol vs. -33.13 ± 3.26 Kcal/mol), and much lower affinities than Delta RBD (-42.76 ± 2.38 Kcal/mol). Further analysis revealed that Omicron N501Y increase ACE2 binding but Q493K and Q498R decrease ACE2 binding. In addition, Omicron RBD might escape the launched monoclonal antibodies (mAbs) Etesevimab and clinical BD-368-2 but may still sensitive to the launched mAbs Bebtelovimab.

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Molecular Dynamics Simulation Study of the Interaction between Human Angiotensin Converting Enzyme 2 and Spike Protein Receptor Binding Domain of the SARS-CoV-2 B.1.617 Variant

Biomolecules ◽

10.3390/biom11081244 ◽

2021 ◽

Vol 11 (8) ◽

pp. 1244

Author(s):

Priya Antony ◽

Ranjit Vijayan

Keyword(s):

Molecular Dynamics ◽

Angiotensin Converting Enzyme ◽

Molecular Dynamics Simulations ◽

Receptor Binding ◽

Binding Domain ◽

Receptor Binding Domain ◽

Converting Enzyme ◽

S Protein ◽

Angiotensin Converting Enzyme 2 ◽

Dynamics Simulations

The COVID-19 pandemic, caused by the SARS-CoV-2 virus, has had a significant impact on people’s daily lives. The rapidly spreading B.1.617 lineage harbors two key mutations—L452R and E484Q—in the receptor binding domain (RBD) of its spike (S) protein. To understand the impact and structural dynamics of the variations in the interface of S protein and its host factor, the human angiotensin-converting enzyme 2 (hACE2), triplicate 500 ns molecular dynamics simulations were performed using single (E484Q or L452R) and double (E484Q + L452R) mutant structures and compared to wild type simulations. Our results indicate that the E484Q mutation disrupts the conserved salt bridge formed between Lys31 of hACE2 and Glu484 of S protein. Additionally, E484Q, which could favor the up conformation of the RBD, may help in enhanced hACE2 binding and immune escape. L452R introduces a charged patch near the binding surface that permits increased electrostatic attraction between the proteins. An improved network of intramolecular interactions observed is likely to increase the stability of the S protein and conformational changes may prevent the binding of neutralizing antibodies. The results obtained from the molecular dynamics simulations suggest that structural and dynamic changes introduced by these variations enhance the affinity of the viral S protein to hACE2 and could form the basis for further studies.

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The flexibility of ACE2 in the context of SARS-CoV-2 infection

10.1101/2020.09.16.300459 ◽

2020 ◽

Cited By ~ 3

Author(s):

E. P. Barros ◽

L. Casalino ◽

Z. Gaieb ◽

A. C. Dommer ◽

Y. Wang ◽

...

Keyword(s):

Molecular Dynamics ◽

Molecular Dynamics Simulations ◽

Receptor Binding ◽

Rational Design ◽

Binding Domain ◽

Full Length ◽

Receptor Binding Domain ◽

Spike Glycoprotein ◽

Linker Region ◽

Dynamics Simulations

AbstractThe COVID-19 pandemic has swept over the world in the past months, causing significant loss of life and consequences to human health. Although numerous drug and vaccine developments efforts are underway, many questions remain outstanding on the mechanism of SARS-CoV-2 viral association to angiotensin-converting enzyme 2 (ACE2), its main host receptor, and entry in the cell. Structural and biophysical studies indicate some degree of flexibility in the viral extracellular Spike glycoprotein and at the receptor binding domain-receptor interface, suggesting a role in infection. Here, we perform all-atom molecular dynamics simulations of the glycosylated, full-length membrane-bound ACE2 receptor, in both an apo and spike receptor binding domain (RBD) bound state, in order to probe the intrinsic dynamics of the ACE2 receptor in the context of the cell surface. A large degree of fluctuation in the full length structure is observed, indicating hinge bending motions at the linker region connecting the head to the transmembrane helix, while still not disrupting the ACE2 homodimer or ACE2-RBD interfaces. This flexibility translates into an ensemble of ACE2 homodimer conformations that could sterically accommodate binding of the spike trimer to more than one ACE2 homodimer, and suggests a mechanical contribution of the host receptor towards the large spike conformational changes required for cell fusion. This work presents further structural and functional insights into the role of ACE2 in viral infection that can be exploited for the rational design of effective SARS-CoV-2 therapeutics.Statement of SignificanceAs the host receptor of SARS-CoV-2, ACE2 has been the subject of extensive structural and antibody design efforts in aims to curtail COVID-19 spread. Here, we perform molecular dynamics simulations of the homodimer ACE2 full-length structure to study the dynamics of this protein in the context of the cellular membrane. The simulations evidence exceptional plasticity in the protein structure due to flexible hinge motions in the head-transmembrane domain linker region and helix mobility in the membrane, resulting in a varied ensemble of conformations distinct from the experimental structures. Our findings suggest a dynamical contribution of ACE2 to the spike glycoprotein shedding required for infection, and contribute to the question of stoichiometry of the Spike-ACE2 complex.

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Curious Binding Energy Increase between the Receptor-Binding Domain of the SARS-CoV-2 Spike Protein and Angiotensin-Converting Enzyme 2 Adsorbed on a Silane Monolayer from Molecular Dynamics Simulations

The Journal of Physical Chemistry B ◽

10.1021/acs.jpcb.1c06050 ◽

2021 ◽

Author(s):

Solène Lecot ◽

Yann Chevolot ◽

Magali Phaner-Goutorbe ◽

Christelle Yeromonahos

Keyword(s):

Molecular Dynamics ◽

Binding Energy ◽

Angiotensin Converting Enzyme ◽

Receptor Binding ◽

Spike Protein ◽

Receptor Binding Domain ◽

Converting Enzyme ◽

Energy Increase ◽

Angiotensin Converting Enzyme 2 ◽

Dynamics Simulations

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Effect of mutation on structure, function and dynamics of receptor binding domain of human SARS-CoV-2 with host cell receptor ACE2: a molecular dynamics simulations study

Journal of Biomolecular Structure and Dynamics ◽

10.1080/07391102.2020.1802348 ◽

2020 ◽

pp. 1-15 ◽

Cited By ~ 2

Author(s):

Budheswar Dehury ◽

Vishakha Raina ◽

Namrata Misra ◽

Mrutyunjay Suar

Keyword(s):

Molecular Dynamics ◽

Structure Function ◽

Molecular Dynamics Simulations ◽

Host Cell ◽

Receptor Binding ◽

Cell Receptor ◽

Binding Domain ◽

Receptor Binding Domain ◽

Host Cell Receptor ◽

Dynamics Simulations

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Experimental evidence for enhanced receptor binding by rapidly spreading SARS-CoV-2 variants

10.1101/2021.02.22.432357 ◽

2021 ◽

Author(s):

Charlie Laffeber ◽

Kelly de Koning ◽

Roland Kanaar ◽

Joyce HG Lebbink

Keyword(s):

Receptor Binding ◽

Immune Evasion ◽

Viral Genome ◽

Double Mutant ◽

Functional Characterization ◽

Host Cells ◽

Receptor Binding Domain ◽

Wild Type ◽

Angiotensin Converting Enzyme 2 ◽

The Uk

AbstractRapidly spreading new variants of SARS-CoV-2 carry multiple mutations in the viral spike protein which attaches to the angiotensin converting enzyme 2 (ACE2) receptor on host cells. Among these mutations are amino acid changes N501Y (lineage B.1.1.7, first identified in the UK), and the combination N501Y, E484K, K417N (B.1.351, first identified in South Africa), all located at the interface on the receptor binding domain (RBD). We experimentally establish that RBD containing the N501Y mutation results in 9-fold stronger binding to the hACE2 receptor than wild type RBD. The E484K mutation does not significantly influence the affinity for the receptor, while K417N attenuates affinity. As a result, RBD from B.1.351 containing all three mutations binds 3-fold stronger to hACE2 than wild type RBD but 3-fold weaker than N501Y. The recently emerging double mutant E484K/N501Y binds as tight as N501Y. The independent evolution of lineages containing mutations with different effects on receptor binding affinity, viral transmission and immune evasion underscores the importance of global viral genome surveillance and functional characterization.

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