Correction: Identifying key determinants and dynamics of SARS-CoV-2/ACE2 tight interaction.
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ABSTRACT:
SUBMITTER: Ngo VA
PROVIDER: S-EPMC8565735 | biostudies-literature | 2021
REPOSITORIES: biostudies-literature
Publications
Correction: Identifying key determinants and dynamics of SARS-CoV-2/ACE2 tight interaction.
PloS one 20211103 11
[This corrects the article DOI: 10.1371/journal.pone.0257905.]. ...[more]
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Project description:SARS-CoV-2 virus, the causative agent of Covid-19, has fired up a global pandemic. The virus interacts with the human receptor angiotensin-converting enzyme 2 (ACE2) for an invasion via receptor binding domain (RBD) on its spike protein. To provide a deeper understanding of this interaction, we performed microsecond simulations of the RBD-ACE2 complex for SARS-CoV-2 and compared it with the closely related SARS-CoV discovered in 2003. We show residues in the RBD of SARS-CoV-2 that were mutated from SARS-CoV, collectively help make the RBD anchor much stronger to the N-terminal part of ACE2 than the corresponding residues on RBD of SARS-CoV. This would result in a reduced dissociation rate of SARS-CoV-2 from human receptor protein compared to SARS-CoV. The phenomenon was consistently observed in simulations beyond 500 ns and was reproducible across different force fields. Altogether, our study adds more insight into the critical dynamics of the key residues at the virus spike and human receptor binding interface and potentially aids the development of diagnostics and therapeutics to combat the pandemic efficiently.
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Project description:Despite sequence similarity to SARS-CoV-1, SARS-CoV-2 has demonstrated greater widespread virulence and unique challenges to researchers aiming to study its pathogenicity in humans. The interaction of the viral receptor binding domain (RBD) with its main host cell receptor, angiotensin-converting enzyme 2 (ACE2), has emerged as a critical focal point for the development of anti-viral therapeutics and vaccines. In this study, we selectively identify and characterize the impact of mutating certain amino acid residues in the RBD of SARS-CoV-2 and in ACE2, by utilizing our recently developed NanoBiT technology-based biosensor as well as pseudotyped-virus infectivity assays. Specifically, we examine the mutational effects on RBD-ACE2 binding ability, efficacy of competitive inhibitors, as well as neutralizing antibody activity. We also look at the implications the mutations may have on virus transmissibility, host susceptibility, and the virus transmission path to humans. These critical determinants of virus-host interactions may provide more effective targets for ongoing vaccines, drug development, and potentially pave the way for determining the genetic variation underlying disease severity.
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Project description:The SARS-CoV-2 coronavirus (COVID-19) that is causing the massive global pandemic exhibits similar human cell invasion mechanism as the coronavirus SARS-CoV, which had significantly lower fatalities. The cell membrane protein Angiotensin-converting enzyme 2 (ACE2) is the initiation point for both the coronavirus infections in humans. Here, we model the molecular interactions and mechanical properties of ACE2 with both SARS-CoV and COVID-19 spike protein receptor-binding domains (RBD). We report that the COVID-19 spike RBD interacts with ACE2 more strongly and at only two protein residues, as compared to multi-residue interaction of the SARS-CoV. Although both coronaviruses stiffen the ACE2, the impact of COVID-19 is six times larger, which points towards differences in the severity of the reported respiratory distress. The recognition of specific residues of ACE2 attachments to coronaviruses is important as the residues suggest potential sites of intervention to inhibit attachment and subsequent entry of the COVID-19 into human host cells.
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Project description:The coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a major public health concern. A handful of static structures now provide molecular insights into how SARS-CoV-2 and SARS-CoV interact with its host target, which is the angiotensin converting enzyme 2 (ACE2). Molecular recognition, binding and function are dynamic processes. To evaluate this, multiple 500 ns or 1 μs all-atom molecular dynamics simulations were performed to better understand the structural stability and interfacial interactions between the receptor binding domain of the spike (S) protein of SARS-CoV-2 and SARS-CoV bound to ACE2. Several contacts were observed to form, break and reform in the interface during the simulations. Our results indicate that SARS-CoV-2 and SARS-CoV utilizes unique strategies to achieve stable binding to ACE2. Several differences were observed between the residues of SARS-CoV-2 and SARS-CoV that consistently interacted with ACE2. Notably, a stable salt bridge between Lys417 of SARS-CoV-2 S protein and Asp30 of ACE2 as well as three stable hydrogen bonds between Tyr449, Gln493 and Gln498 of SARS-CoV-2 and Asp38, Glu35 and Lys353 of ACE2 were observed, which were absent in the ACE2-SARS-CoV interface. Some previously reported residues, which were suggested to enhance the binding affinity of SARS-CoV-2, were not observed to form stable interactions in these simulations. Molecular mechanics-generalized Born surface area based free energy of binding was observed to be higher for SARS-CoV-2 in all simulations. Stable binding to the host receptor is crucial for virus entry. Therefore, special consideration should be given to these stable interactions while designing potential drugs and treatment modalities to target or disrupt this interface.
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Project description:Severe acute respiratory syndrome virus 2 (SARS-CoV-2) is responsible for the current global coronavirus disease 2019 (COVID-19) pandemic, infecting millions of people and causing hundreds of thousands of deaths. The viral entry of SARS-CoV-2 depends on an interaction between the receptor-binding domain of its trimeric spike glycoprotein and the human angiotensin-converting enzyme 2 (ACE2) receptor. A better understanding of the spike/ACE2 interaction is still required to design anti-SARS-CoV-2 therapeutics. Here, we investigated the degree of cooperativity of ACE2 within both the SARS-CoV-2 and the closely related SARS-CoV-1 membrane-bound S glycoproteins. We show that there exist differential inter-protomer conformational transitions between both spike trimers. Interestingly, the SARS-CoV-2 spike exhibits a positive cooperativity for monomeric soluble ACE2 binding when compared to the SARS-CoV-1 spike, which might have more structural restraints. Our findings can be of importance in the development of therapeutics that block the spike/ACE2 interaction.
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Project description:We compared the electrostatic properties of the spike proteins (S-proteins) of three coronaviruses, SARS-CoV, MERS-CoV, and SARS-CoV-2, and their interactions with photosensitizers (PSs), octacationic octakis(cholinyl)zinc phthalocyanine (Zn-PcChol8+) and monocationic methylene blue (MB). We found a major common PS binding site at the connection of the S-protein stalk and head. The molecules of Zn-PcChol8+ and MB also form electrostatic encounter complexes with large area of negative electrostatic potential at the head of the S-protein of SARS-CoV-2, between fusion protein and heptad repeat 1 domain. The top of the SARS-CoV spike head demonstrates a notable area of electrostatic contacts with Zn-PcChol8+ and MB that corresponds to the N-terminal domain. The S-protein protomers of SARS-CoV-2 in "open" and "closed" conformations demonstrate different ability to attract PS molecules. In contrast with Zn-PcChol8+, MB possesses the ability to penetrate inside the pocket formed as a result of SARS-CoV-2 receptor binding domain transition into the "open" state. The existence of binding site for cationic PSs common to the S-proteins of SARS-CoV, SARS-CoV-2, and MERS-CoV creates prospects for the wide use of this type of PSs to combat the spread of coronaviruses.
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