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

2020 ◽  
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.

scholarly journals 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 ◽  
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.

scholarly journals 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

2021 ◽  
Author(s):  
Leyun Wu ◽  
Liping Zhou ◽  
Mengxia Mo ◽  
Yishui Li ◽  
Jiaxin Han ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Receptor Binding ◽  
Immune Evasion ◽  
Binding Motif ◽  
Binding Affinities ◽  
Receptor Binding Domain ◽  
Wild Type ◽  
Angiotensin Converting Enzyme 2 ◽  
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.

scholarly journals A comparative survey of betacoronavirus strain molecular dynamics identifies key ACE2 binding sites

2020 ◽  
Author(s):  
P. X. Rynkiewicz ◽  
G. A. Babbitt ◽  
F. Cui ◽  
A. O. Hudson ◽  
M. L. Lynch
Keyword(s):  
Molecular Dynamics ◽  
Receptor Binding ◽  
Acid Sites ◽  
Binding Domain ◽  
Site Directed Mutagenesis ◽  
Receptor Binding Domain ◽  
Spike Glycoprotein ◽  
Binding Interactions ◽  
Interaction Site ◽  
Target Proteins

ABSTRACTComparative functional analysis of the binding interactions between various betacoronavirus strains and their potential human target proteins, such as ACE1, ACE2 and CD26, is critical to our future understanding and combating of COVID-19. Here, employing large replicate sets of GPU accelerated molecular dynamics simulations, we statistically compare atom fluctuations of the known human target proteins in both the presence and absence of different strains of the viral receptor binding domain (RBD) of the S spike glycoprotein. We identify a common interaction site between the N-terminal helices of ACE2 and the viral RBD in all strains (hCoV-OC43, hCoV-HKU1, MERS-CoV, SARS-CoV1, and SARS-CoV-2) and a second more dynamically complex RBD interaction site involving the ACE2 amino acid sites K353, Q325, and a novel motif, AAQPFLL (386-392) in the more recent cross-species spillovers (i.e. absent in hCoV-OC43). We use computational mutagenesis to further confirm the functional relevance of these sites. We propose a “one touch/two touch” model of viral evolution potentially involved in functionally facilitating binding interactions in zoonotic spillovers. We also observe these two touch sites governing RBD binding activity in simulations on hybrid models of the suspected viral progenitor, batCoV-HKU4, interacting with both the human SARS target, ACE2, and the human MERS target, CD26. Lastly, we confirm that the presence of a common hypertension drug (lisinopril) within the target site of SARS-CoV-2 bound models of ACE1 and ACE2 acts to enhance the RBD interactions at the same key sites in our proposed model. In the near future, we recommend that our comparative computational analysis identifying these key viral RBD-ACE2 binding interactions be supplemented with comparative studies of site-directed mutagenesis in order to screen for current and future coronavirus strains at high risk of zoonotic transmission to humans.STATEMENT OF SIGNIFICANCEWe generated structural models of the spike glycoprotein receptor binding domain from recent and past betacoronavirus outbreak strains aligned to the angiotensin 1 converting enzyme 2 protein, the primary target protein of the SARS-CoV-2 virus causing COVID 19. We then statistically compared computer simulated molecular dynamics of viral bound and unbound versions of each model to identify locations where interactions with each viral strain have dampened the atom fluctuations during viral binding. We demonstrate that all known strains of betacoronavirus are strongly interactive with the N-terminal helix region of ACE2. We also identify a more complex viral interaction with three novel sites that associates with more recent and deadly SARS strains, and also a bat progenitor strain HKU4.

Role of key point Mutations in Receptor Binding Domain of SARS-CoV-2 Spike Glycoprotein

2020 ◽  
Vol 20 ◽  
Author(s):  
Bipin Singh
Keyword(s):  
Receptor Binding ◽  
Point Mutations ◽  
Binding Domain ◽  
Receptor Binding Domain ◽  
Spike Glycoprotein ◽  
Angiotensin Converting Enzyme 2 ◽  
Recent Outbreak ◽  
Novel Coronavirus ◽  
Genomic Similarity

: The recent outbreak of novel coronavirus (SARS-CoV-2 or 2019-nCoV) and its worldwide spread is posing one of the major threats to human health and the world economy. It has been suggested that SARS-CoV-2 is similar to SARSCoV based on the comparison of the genome sequence. Despite the genomic similarity between SARS-CoV-2 and SARSCoV, the spike glycoprotein and receptor binding domain in SARS-CoV-2 shows the considerable difference compared to SARS-CoV, due to the presence of several point mutations. The analysis of receptor binding domain (RBD) from recently published 3D structures of spike glycoprotein of SARS-CoV-2 (Yan, R., et al. (2020); Wrapp, D., et al. (2020); Walls, A. C., et al. (2020)) highlights the contribution of a few key point mutations in RBD of spike glycoprotein and molecular basis of its efficient binding with human angiotensin-converting enzyme 2 (ACE2).

scholarly journals Protein unfolding by SDS: the microscopic mechanisms and the properties of the SDS-protein assembly

Nanoscale ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 5422-5434 ◽  
Author(s):  
David Winogradoff ◽  
Shalini John ◽  
Aleksei Aksimentiev
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Anionic Surfactant ◽  
Protein Unfolding ◽  
Protein Assembly ◽  
Full Length ◽  
Dynamics Simulations

Molecular dynamics simulations reveal how anionic surfactant SDS and heat unfold full-length proteins.

ReaxFF-based molecular dynamics simulation of the interaction between plasma ROS and the receptor-binding domain of the spike protein in the capsid protein of SARS-CoV-2

2021 ◽  
Author(s):  
Huichao Wang ◽  
Tong Zhao ◽  
Shuhui Yang ◽  
Liang Zou ◽  
Xiaolong Wang ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Amino Acid ◽  
Capsid Protein ◽  
Receptor Binding ◽  
Hydrogen Abstraction ◽  
Binding Domain ◽  
Spike Protein ◽  
Receptor Binding Domain ◽  
Amino Acid Residues ◽  
Global Epidemic

Abstract Under the severe situation of the current global epidemic, researchers have been working hard to find a reliable way to suppress the infection of the virus and prevent the spread of the epidemic. Studies have shown that the recognition and binding of human angiotensin-converting enzyme 2 (ACE2) by the receptor-binding domain (BRD) of spike protein on the surface of SARS-CoV-2 is a crucial step for SARS-CoV-2 to invade human receptor cells, and blocking this process can inhibit the virus from invading human normal cells. Plasma treatment can disrupt the structure of the RBD and effectively block the binding process. However, the mechanism by which plasma blocks the recognition and binding between the two is not clear. In this study, reaction process between reactive oxygen species (ROS) in plasma and the molecular model of RBD was simulated using a reactive molecular dynamics method. The results showed that the destruction of RBD molecule by ROS was triggered by hydrogen abstraction reactions. O and OH abstracted H atoms from RBD, while the H atoms of H2O2 and HO2 were abstracted by RBD. The hydrogen abstraction resulted in the breakage of C-H, N-H, O-H and C=O bonds and the formation of C=C, C=N bonds. The addition reaction of OH increased the number of O-H bonds and caused the formation of C-O, N-O and O-H bonds. The dissociation of N-H bonds led to the destruction of the original structure of peptide bonds and amino acid residues, change the type of amino acid residues, and caused the conversion of N-C and N=C, C=O and C-O. The simulation partially elucidated the microscopic mechanism of the interaction between ROS in plasma and the capsid protein of SARS-CoV-2, providing theoretical support for the control of SARS-CoV-2 infection by plasma, a contribution to overcoming the global epidemic problem.

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