Why Does the Novel Coronavirus Spike Protein Interact so Strongly with the Human ACE2? A Thermodynamic Answer

Andrade, Jones de; Gonçalves, Paulo Fernando Bruno; Netz, Paulo Augusto

doi:10.1002/cbic.202000455

Cited by 30 publications

(39 citation statements)

References 36 publications

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“…Compared to −16.04 kcal/mol binding free energy of the prototype SARS-CoV-2 RBD system, three mutant types, N354D/D364Y, D364Y and V367F, showed significant lower \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{upgreek} \usepackage{mathrsfs} \setlength{\oddsidemargin}{-69pt} \begin{document} }{}$\Delta G$\end{document} values indicating the significant higher binding affinities with hACE2. Two of these three mutants, N354D/D364Y and V367F, have drawn extensive attention as they showed up in multiple countries, indicating its enhanced binding affinity in the real world [ 28 ]. Four mutant types showed comparable binding affinity with the wild type, which are V341I, A435S, W436R and V483A.…”

Section: Resultsmentioning

confidence: 99%

“…[ 27 ] employed MD simulation to help understand the ionic effects on wild RBD/hACE2 complex formation/stability and reported two regions on wild RBD, which can interact with hACE2 differently; de Andrade et al . [ 28 ] reported the binding affinities of wild SARS-CoV spike protein and wild SARS-CoV-2 spike protein with hACE2 and provided detailed analysis to help gain a clearer view on the binding process between two viruses. All of these studies focused on the wild type of SARS-Cov-2 spike protein.…”

Section: Introductionmentioning

confidence: 99%

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In silico binding profile characterization of SARS-CoV-2 spike protein and its mutants bound to human ACE2 receptor

Zhang

Zhai

et al. 2021

Briefings in Bioinformatics

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Severe acute respiratory syndrome coronavirus (SARS-CoV-2), a novel coronavirus, has brought an unprecedented pandemic to the world and affected over 64 million people. The virus infects human using its spike glycoprotein mediated by a crucial area, receptor-binding domain (RBD), to bind to the human ACE2 (hACE2) receptor. Mutations on RBD have been observed in different countries and classified into nine types: A435S, D364Y, G476S, N354D/D364Y, R408I, V341I, V367F, V483A and W436R. Employing molecular dynamics (MD) simulation, we investigated dynamics and structures of the complexes of the prototype and mutant types of SARS-CoV-2 spike RBDs and hACE2. We then probed binding free energies of the prototype and mutant types of RBD with hACE2 protein by using an end-point molecular mechanics Poisson Boltzmann surface area (MM-PBSA) method. According to the result of MM-PBSA binding free energy calculations, we found that V367F and N354D/D364Y mutant types showed enhanced binding affinities with hACE2 compared to the prototype. Our computational protocols were validated by the successful prediction of relative binding free energies between prototype and three mutants: N354D/D364Y, V367F and W436R. Thus, this study provides a reliable computational protocol to fast assess the existing and emerging RBD mutations. More importantly, the binding hotspots identified by using the molecular mechanics generalized Born surface area (MM-GBSA) free energy decomposition approach can guide the rational design of small molecule drugs or vaccines free of drug resistance, to interfere with or eradicate spike-hACE2 binding.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

In silico binding profile characterization of SARS-CoV-2 spike protein and its mutants bound to human ACE2 receptor

Zhang

Zhai

et al. 2021

Briefings in Bioinformatics

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“…Several glycosylation sites are near the binding interface (7,9,14,15). Whereas the focus has largely been on amino acid interactions in the ACE2-spike binding interface (16,17), the role of glycosylation in binding has been recognized (7,(18)(19)(20). The extracellular domain of the ACE2 receptor has seven N-glycosylation sites (N53, N90, N103, N322, N432, N546, and N690) and several O-glycosylation sites (e.g., T730) (9,14).…”

Section: Virus-host Interactionmentioning

confidence: 99%

Dual nature of human ACE2 glycosylation in binding to SARS-CoV-2 spike

Mehdipour

Hummer

2021

Proc. Natl. Acad. Sci. U.S.A.

137

147

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Binding of the spike protein of SARS-CoV-2 to the human angiotensin-converting enzyme 2 (ACE2) receptor triggers translocation of the virus into cells. Both the ACE2 receptor and the spike protein are heavily glycosylated, including at sites near their binding interface. We built fully glycosylated models of the ACE2 receptor bound to the receptor binding domain (RBD) of the SARS-CoV-2 spike protein. Using atomistic molecular dynamics (MD) simulations, we found that the glycosylation of the human ACE2 receptor contributes substantially to the binding of the virus. Interestingly, the glycans at two glycosylation sites, N90 and N322, have opposite effects on spike protein binding. The glycan at the N90 site partly covers the binding interface of the spike RBD. Therefore, this glycan can interfere with the binding of the spike protein and protect against docking of the virus to the cell. By contrast, the glycan at the N322 site interacts tightly with the RBD of the ACE2-bound spike protein and strengthens the complex. Remarkably, the N322 glycan binds to a conserved region of the spike protein identified previously as a cryptic epitope for a neutralizing antibody. By mapping the glycan binding sites, our MD simulations aid in the targeted development of neutralizing antibodies and SARS-CoV-2 fusion inhibitors.

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“…Accommodation of such pocket could permit distrusted glycan stability within such site being at proximity to the h ACE2/SARS-CoV-2 Spike protein receptor-binding domain (RBD) interface. Accommodating this site by small molecules may impact the SARS-CoV-2 Spike protein owing to the reported findings of the glycan-mediated influence/interference with the h ACE2/SARS-CoV-2 Spike protein association as well as spike epitopic recognition (Li et al, 2005 ; Banerjee et al, 2020 ; de Andrade et al, 2020 ; Devaux et al, 2020 ; Grant et al, 2020 ). Therefore, the affinity of ACEIs against the h ACE2-NAG binding site was investigating through molecular docking and dynamics studies having the glycan NAG as a competitor binder and reference ligand.…”

Section: Introductionmentioning

confidence: 99%

Molecular Docking and Dynamics Simulation Revealed the Potential Inhibitory Activity of ACEIs Against SARS-CoV-2 Targeting the hACE2 Receptor

et al. 2021

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The rapid and global spread of a new human coronavirus, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has produced an immediate urgency to discover promising targets for the treatment of COVID-19. Here, we consider drug repurposing as an attractive approach that can facilitate the drug discovery process by repurposing existing pharmaceuticals to treat illnesses other than their primary indications. We review current information concerning the global health issue of COVID-19 including promising approved drugs, e.g., human angiotensin-converting enzyme inhibitors (hACEIs). Besides, we describe computational approaches to be used in drug repurposing and highlight examples of in-silico studies of drug development efforts against SARS-CoV-2. Alacepril and lisinopril were found to interact with human angiotensin-converting enzyme 2 (hACE2), the host entranceway for SARS-CoV-2 spike protein, through exhibiting the most acceptable rmsd_refine values and the best binding affinity through forming a strong hydrogen bond with Asn90, which is assumed to be essential for the activity, as well as significant extra interactions with other receptor-binding residues. Furthermore, molecular dynamics (MD) simulations followed by calculation of the binding free energy were also carried out for the most promising two ligand-pocket complexes from docking studies (alacepril and lisinopril) to clarify some information on their thermodynamic and dynamic properties and confirm the docking results as well. These results we obtained probably provided an excellent lead candidate for the development of therapeutic drugs against COVID-19. Eventually, animal experiments and accurate clinical trials are needed to confirm the potential preventive and treatment effect of these compounds.

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Why Does the Novel Coronavirus Spike Protein Interact so Strongly with the Human ACE2? A Thermodynamic Answer

Cited by 30 publications

References 36 publications

In silico binding profile characterization of SARS-CoV-2 spike protein and its mutants bound to human ACE2 receptor

In silico binding profile characterization of SARS-CoV-2 spike protein and its mutants bound to human ACE2 receptor

Dual nature of human ACE2 glycosylation in binding to SARS-CoV-2 spike

Molecular Docking and Dynamics Simulation Revealed the Potential Inhibitory Activity of ACEIs Against SARS-CoV-2 Targeting the hACE2 Receptor

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