Enhanced receptor binding of SARS-CoV-2 through networks of hydrogen-bonding and hydrophobic interactions

Wang, Yingjie; Liu, Meiyi; Gao, Jiali

doi:10.1073/pnas.2008209117

Cited by 317 publications

(453 citation statements)

References 46 publications

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“…using FEP. 47 In addition, this mutation was shown to be among the five mutations that produce a super affinity ACE2 binder based on SARS-COV RBD. 6 Alanine mutations at residues Y449, G447 and E484 increased the motion in is the reason for higher binding energy of mutant Y489A than wild-type complex.…”

Section: Discussionmentioning

confidence: 98%

“…52 The critical role of interface residues and residues are computationally investigated here and in other articles and the results of all the studies indicate the importance of these residues for the stability of the complex and finding hotspot residues for the interaction with receptor ACE2. 47,[52][53][54] It is interesting to note the role of shown there is a correlation between higher binding affinity to receptor and higher infection rate by coronavirus. [55][56][57][58] High binding affinity for some mutants such as T478I could be the reason for higher human-to-human transmission rate in regions where these mutations are found.…”

Section: Discussionmentioning

confidence: 99%

“…This residue is V404 in SARS-COV which is not able to make any salt-bridge and does not make H-bond with ACE2. Wang et al 47 used a free energy perturbation (FEP) approach and showed that mutation V404 to K417 increases the binding affinity of nCOV-2019 RBD to ACE2 by…”

Section: Binding Free Energiesmentioning

confidence: 99%

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Critical Sequence Hot-spots for Binding of nCOV-2019 to ACE2 as Evaluated by Molecular Simulations

Ghorbani

Brooks

Klauda

2020

Preprint

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The novel coronavirus (nCOV-2019) outbreak has put the world on edge, causing millions of cases and hundreds of thousands of deaths all around the world, as of June 2020, let alone the societal and economic impacts of the crisis. The spike protein of nCOV-2019 resides on the virion's surface mediating coronavirus entry into host cells by binding its receptor binding domain (RBD) to the host cell surface receptor protein, angiotensin converter enzyme (ACE2).Our goal is to provide a detailed structural mechanism of how nCOV-2019 recognizes and establishes contacts with ACE2 and its difference with an earlier coronavirus SARS-COV in 2002 via extensive molecular dynamics (MD) simulations. Numerous mutations have been identified in the RBD of nCOV-2019 strains isolated from humans in different parts of the world.In this study, we investigated the effect of these mutations as well as other Ala-scanning mutations on the stability of RBD/ACE2 complex. It is found that most of the naturallyoccurring mutations to the RBD either strengthen or have the same binding affinity to ACE2 as the wild-type nCOV-2019. This may have implications for high human-to-human transmission of coronavirus in regions where these mutations have been found as well as any vaccine design endeavors since these mutations could act as antibody escape mutants. Furthermore, in-silico Ala-scanning and long-timescale MD simulations, highlight the crucial role of the residues at the interface of RBD and ACE2 that may be used as potential pharmacophores for any drug development endeavors. From an evolutional perspective, this study also identifies how the virus has evolved from its predecessor SARS-COV and how it could further evolve to become more infectious.

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

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Critical Sequence Hot-spots for Binding of nCOV-2019 to ACE2 as Evaluated by Molecular Simulations

Ghorbani

Brooks

Klauda

2020

Preprint

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“…Hence, atomistic-level comparison is needed between these two viruses. A recent study found that the hydrogen bonding network and the hydrophobic interactions are major dominating forces that are responsible for enhanced binding in SARS-CoV-2 19 . Till now most of the studies focus on the search for new vaccines and drug molecules against COVID-19.…”

Section: Introductionmentioning

confidence: 99%

Interfacial Water Molecules Make RBD of SPIKE Protein and Human ACE2 to Stick Together

Malik¹,

Prahlad²,

Kulkarni³

et al. 2020

Preprint

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A novel coronavirus (SARS-CoV-2; COVID-19) that initially originates from Wuhan province in China has emerged as a global pandemic, an outbreak that started at the end of 2019 which claims 431,192 (Date: 15 th June 2020 (https://covid19.who.in) life till now. Since then scientists all over the world are engaged in developing new vaccines, antibodies, or drug molecules to combat this new threat. Here in this work, we performed an in-silico analysis on the protein-protein interactions between the receptor-binding (RBD) domain of viral SPIKE protein and human angiotensinconverting enzyme 2 (hACE2) receptor to highlight the key alteration that happened from SARS-CoV to SARS-CoV-2. We analyzed and compared the molecular differences between these two viruses by using various computational approaches such as binding affinity calculations, computational alanine, and molecular dynamics simulations. The binding affinity calculations show SARS-CoV-2 binds little more firmly to the hACE2 receptor than that of SARS-CoV. Analysis of simulation trajectories reveals that enhanced hydrophobic contacts or the van derWaals interaction play a major role in stabilizing the protein-protein interface. The major finding obtained from molecular dynamics simulations is that the RBD-ACE2 interface is populated with water molecules and interacts strongly with both RBD and ACE2 interfacial residues during the simulation periods. We also emphasize that the interfacial water molecules play a critical role in binding and maintaining the stability of the RBD/hACE2 complex. The water-mediated hydrogen bond by the bridge water molecules is crucial for stabilizing the RBD and ACE2 domains. The structural and dynamical features presented here may serve as a guide for developing new drug molecules, vaccines, or antibodies to combat the COVID-19 pandemic.

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“…Furthermore, as we demonstrate in this study, ACE2 is a potent inhibitor of neutralizing antibody binding to the SARS-CoV-2 spike protein receptor binding domain, and this may relate to why short-lived antibody responses are a hallmark component of SARS-CoV-1 infections in many patients, whereby SARS-CoV-2 exhibits as much as 10-15x stronger binding to ACE2 than SARS-CoV-1 and would likely exhibit even stronger antibody maturation issues according to this hypothesis. 40,41,42,43 Therapeutics that mimic ACE2 and shield this key epitope are likely to bias antibody formation towards off-target sites, which could contribute to antibody-dependent enhancement (ADE), vaccine-associated enhanced respiratory distress (VAERD), and a host of other immunological issues upon repeat viral challenge. 44,45,46,47,48,49,50,51,52,52 With SARS-CoV-1, a marked lack of peripheral memory B cell responses was observed in patients 6 years following infection.…”

Section: Discussionmentioning

confidence: 99%

Peptide Antidotes to SARS-CoV-2 (COVID-19)

Watson

Ferreira

Hwang

et al. 2020

Preprint

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The design of an immunogenic scaffold that serves a role in treating a pathogen, and can be rapidly and predictively modeled, has remained an elusive feat. Here, we demonstrate that SARS-BLOCK™ synthetic peptide scaffolds act as antidotes to SARS-CoV-2 spike protein-mediated infection of human ACE2-expressing cells. Critically, SARS-BLOCK™ peptides are able to potently and competitively inhibit SARS-CoV-2 S1 spike protein receptor binding domain (RBD) binding to ACE2, the main cellular entry pathway for SARS-CoV-2, while also binding to neutralizing antibodies against SARS-CoV-2. In order to create this potential therapeutic antidote-vaccine, we designed, simulated, synthesized, modeled epitopes, predicted peptide folding, and characterized behavior of a novel set of synthetic peptides. The biomimetic technology is modeled off the receptor binding motif of the SARS-CoV-2 coronavirus, and modified to provide enhanced stability and folding versus the truncated wildtype sequence. These novel peptides attain single-micromolar binding affinities for ACE2 and a neutralizing antibody against the SARS-CoV-2 receptor binding domain (RBD), and demonstrate significant reduction of infection in nanomolar doses. We also demonstrate that soluble ACE2 abrogates binding of RBD to neutralizing antibodies, which we posit is an essential immune-evasive mechanism of the virus. SARS-BLOCK™ is designed to “uncloak” the viral ACE2 coating mechanism, while also binding to neutralizing antibodies with the intention of stimulating a specific neutralizing antibody response. Our peptide scaffolds demonstrate promise for future studies evaluating specificity and sensitivity of immune responses to our antidote-vaccine. In summary, SARS-BLOCK™ peptides are a promising COVID-19 antidote designed to combine the benefits of a therapeutic and vaccine, effectively creating a new generation of prophylactic and reactive antiviral therapeutics whereby immune responses can be enhanced rather than blunted.

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Enhanced receptor binding of SARS-CoV-2 through networks of hydrogen-bonding and hydrophobic interactions

Cited by 317 publications

References 46 publications

Critical Sequence Hot-spots for Binding of nCOV-2019 to ACE2 as Evaluated by Molecular Simulations

Critical Sequence Hot-spots for Binding of nCOV-2019 to ACE2 as Evaluated by Molecular Simulations

Interfacial Water Molecules Make RBD of SPIKE Protein and Human ACE2 to Stick Together

Peptide Antidotes to SARS-CoV-2 (COVID-19)

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