Binding Interactions between RBD of Spike-Protein and Human ACE2 in Omicron variant

Jawad, Bahaa; Adhikari, Puja; Podgornik, Rudolf; Ching, W. Y.

doi:10.1101/2022.02.10.480009

Cited by 4 publications

(11 citation statements)

References 45 publications

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“…However, this computational tool gives comparably low binding energies of peptide-protein docking due to the molecular size, high flexibility, and complexing conformation of the peptide ligand, in addition to the simplification of the analysis of ADV (the electrostatic and solvation potentials are neglected, while van der Waals potential, the nondirectional hydrogen bond term, the hydrophobic term, and a conformational entropy penalty are considered) [20,21]. It can be observed that the binding energy values (Table 1 and Table 2) are significantly lower than the binding energies reported in similar works [6,60,61]. For instance, the experimental and theoretical values of the binding energy reported for ACE2-RBD is around −12.0 kcal/mol, which is higher than the binding energy of −4.6 kcal/mol given here [61].…”

Section: Binding Energy By Protein Binding Energy Predictionmentioning

confidence: 87%

“…For instance, the experimental and theoretical values of the binding energy reported for ACE2-RBD is around −12.0 kcal/mol, which is higher than the binding energy of −4.6 kcal/mol given here [61]. Therefore, the PRODIGY web server was used to estimate the binding energy for peptide-RBD docking, since it has been demonstrated that PRODIGY can produce results comparable with those obtained experimentally and most standard in silico analyses [38][39][40]60].…”

Section: Binding Energy By Protein Binding Energy Predictionmentioning

confidence: 96%

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Design and selection of peptides to block the SARS-CoV-2 receptor binding domain by molecular docking

Ramirez-Acosta¹,

Rosales-Fuerte²,

Perez-Sanchez³

et al. 2022

Beilstein J. Nanotechnol.

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The novel Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) is currently one of the most contagious viruses in existence and the cause of the worst pandemic in this century, COVID-19. SARS-CoV-2 infection begins with the recognition of the cellular receptor angiotensin converting enzyme-2 by its spike glycoprotein receptor-binding domain (RBD). Thus, the use of small peptides to neutralize the infective mechanism of SARS-CoV-2 through the RBD is an interesting strategy. The binding ability of 104 peptides (University of Nebraska Medical Center’s Antimicrobial Peptide Database) to the RBD was assessed using molecular docking. Based on the molecular docking results, peptides with great affinity to the RBD were selected. The most common amino acids involved in the recognition of the RBD were identified to design novel peptides based on the number of hydrogen bonds that were formed. At physiological pH, these peptides are almost neutral and soluble in aqueous media. Interestingly, several peptides showed the capability to bind to the active surface area of the RBD of the Wuhan strain, as well as to the RBD of the Delta variant and other SARS-Cov-2 variants. Therefore, these peptides have promising potential in the treatment of the COVID-19 disease caused by different variants of SARS-CoV-2. This research work will be focused on the molecular docking of peptides by molecular dynamics, in addition to an analysis of the possible interaction of these peptides with physiological proteins. This methodology could be extended to design peptides that are active against other viruses.

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Section: Binding Energy By Protein Binding Energy Predictionmentioning

confidence: 87%

Section: Binding Energy By Protein Binding Energy Predictionmentioning

confidence: 96%

Design and selection of peptides to block the SARS-CoV-2 receptor binding domain by molecular docking

Ramirez-Acosta¹,

Rosales-Fuerte²,

Perez-Sanchez³

et al. 2022

Beilstein J. Nanotechnol.

View full text Add to dashboard Cite

show abstract

“…For example, relative to WT, the net positive charge on each RBD increases by two and three for Delta and Omicron variants, respectively. This increase in charge is accompanied both by higher infection rate and reduced potency of neutralizing antibodies [4][5][6][7][8][9][10][11][12]. Both effects are consistent with evolutionary pressure toward RBD mutations which increase positive charge: Firstly, as hACE2 is a charge negative entity [13] thus the electrostatic interaction is increased; and secondly, the electrostatic surfaces of neutralizing antibodies reveal that most antibodies have positively charged RBD-recognition domains.…”

Section: Introductionmentioning

confidence: 83%

Structure adaptation in Omicron SARS-CoV-2/hACE2: Biophysical origins of evolutionary driving forces

Hsiao

Taddese

Jimenez-Serratos

et al. 2022

Preprint

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Since its emergence, the Covid19 pandemic has been sustained by a series of transmission waves initiated by new variants of the SARS-CoV-2 virus. Some of these arise with higher transmissivity and/or increased disease severity. Here we use molecular dynamics simulations to examine the modulation of the fundamental interactions between the receptor binding domain (RBD) of the spike glycoprotein and the host cell receptor (human angiotensin-converting enzyme 2: hACE2) arising from Omicron variant mutations (BA.1 and BA.2) relative to the original wild type strain. We find significant structural differences in the complexes which overall bring the spike protein and its receptor into closer proximity. These are consistent with and attributed to the higher positive charge on the RBD conferred by BA.1 and BA.2 mutations relative to the wild type. However, further differences between sub-variants BA.1 and BA.2 (which have equivalent RBD charges) are also evident: Mutations affect interdomain interactions between the up-chain and its clockwise neighbor chain, resulting in enhanced flexibility for BA.2. Consequently, additional close contacts arise in BA.2 which include binding to hACE2 by a second spike protein monomer, in addition to the up-chain - a motif not found in BA.1. Finally, the mechanism by which the glycans stabilize the up state of the Spike protein differs for the wild type and the Omicrons. We also found the glycan on N90 of hACE2 turns from inhibiting, to facilitating the binding to Omicron spike protein. These structural and electrostatic differences offer further insight into the mechanisms by which viral mutations modulate host cell binding and provide a biophysical basis for evolutionary driving forces.

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“…In this case, it formed an additional salt bridge with Asp38. Interactions with Tyr41 and Gln42 of ACE-2 were stronger compared to WT spike interaction [25].…”

Section: Details About Mutational Effect On the Rbd-ace2 Interactionsmentioning

confidence: 89%

“…Spike variants with mutations like N440K and G476S are high a nity ACE-2 binders and are located in solvent accessible loop regions. Compared to WT spike, both mutations lead to drastic conformational alterations wherein, it reorients the RBM loop towards the binding interface thereby allowing additional interactions [25,26]. Deleterious mutations like G446S and Y505H were also high a nity binders to ACE-2 but was found to be destabilizing for RBD [25,27].…”

Section: Details About Mutational Effect On the Rbd-ace2 Interactionsmentioning

confidence: 99%

Structural perspective of the interactions of ACE2 and SARS CoV-2 Spike protein RBD

Borkotoky

Dey

Hazarika

2022

Preprint

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Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has caused millions of infections and deaths worldwide since its discovery in late 2019 in Wuhan, China. The receptor-binding domain (RBD) of the SARS-CoV-2 spike protein binds to the human angiotensin-converting enzyme-2 (ACE2) receptor, a critical component of the renin-angiotensin system (RAS) that initiates viral transmission. Most of the critical mutations found in SARS CoV-2 are associated with the RBD of the spike protein. The mutations have the potential to reduce the efficacy of vaccines and neutralizing antibodies. Preventing the interaction between Spike RBD and ACE2 is considered a viable therapeutic strategy since ACE2 binding by RBD is the first step in virus infection. Because the interactions between the two entities are critical for both viral transmission and therapeutic development, it is essential to understand their interactions in detail. In this review, the structural details of ACE2, RBD and their interactions are discussed. In addition, some critical mutations of RBD and their impact on ACE2-RBD interactions are also discussed.

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Binding Interactions between RBD of Spike-Protein and Human ACE2 in Omicron variant

Cited by 4 publications

References 45 publications

Design and selection of peptides to block the SARS-CoV-2 receptor binding domain by molecular docking

Design and selection of peptides to block the SARS-CoV-2 receptor binding domain by molecular docking

Structure adaptation in Omicron SARS-CoV-2/hACE2: Biophysical origins of evolutionary driving forces

Structural perspective of the interactions of ACE2 and SARS CoV-2 Spike protein RBD

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