A “Deep Dive” into the SARS-Cov-2 Polymerase Assembly: Identifying Novel Allosteric Sites and Analyzing the Hydrogen Bond Networks and Correlated Dynamics

Barakat, Khaled; Ahmed, Marawan; Tabana, Yasser; Ha, Minwoo

doi:10.1101/2020.06.02.130849

Cited by 7 publications

(3 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We also note that our analysis is limited by necessity to comparison of co-circulating lineages with multiple substitutions shared by common descent (not only D614G), and it is impossible to disentangle effects of substitutions shared between lineages. One amino acid replacement is notable: RdRp P323L, occurred almost concurrently with D614G, and is in almost perfect linkage equilibrium with 614, although the biological effect and likely significance of this change is yet to be determined [21] .…”

Section: Discussionmentioning

confidence: 99%

Evaluating the effects of SARS-CoV-2 Spike mutation D614G on transmissibility and pathogenicity

Volz

Hill

McCrone

et al. 2020

Preprint

281

312

View full text Add to dashboard Cite

In February 2020 a substitution at the interface between SARS-CoV-2 Spike protein subunits, Spike D614G, was observed in public databases. The Spike 614G variant subsequently increased in frequency in many locations throughout the world. Global patterns of dispersal of Spike 614G are suggestive of a selective advantage of this variant, however the origin of Spike 614G is associated with early colonization events in Europe and subsequent radiations to the rest of the world. Increasing frequency of 614G may therefore be due to a random founder effect. We investigate the hypothesis for positive selection of Spike 614G at the level of an individual country, the United Kingdom, using more than 25,000 whole genome SARS-CoV-2 sequences collected by COVID-19 Genomics UK Consortium. Using phylogenetic analysis, we identify Spike 614G and 614D clades with unique origins in the UK and from these we extrapolate and compare growth rates of co-circulating transmission clusters. We find that Spike 614G clusters are introduced in the UK later on average than 614D clusters and grow to larger size after adjusting for time of introduction. Phylodynamic analysis does not show a significant increase in growth rates for clusters with the 614G variant, but population genetic modelling indicates that 614G increases in frequency relative to 614D in a manner consistent with a selective advantage. We also investigate the potential influence of Spike 614D versus G on virulence by matching a subset of records to clinical data on patient outcomes. We do not find any indication that patients infected with the Spike 614G variant have higher COVID-19 mortality, but younger patients have slightly increased odds of 614G carriage. Despite the availability of a very large data set, well represented by both Spike 614 variants, not all approaches showed a conclusive signal of higher transmission rate for 614G, but significant differences in growth, size, and composition of these lineages indicate a need for continued study.

show abstract

Section: Discussionmentioning

confidence: 99%

Evaluating the effects of SARS-CoV-2 Spike mutation D614G on transmissibility and pathogenicity

Volz

Hill

McCrone

et al. 2020

Preprint

281

312

View full text Add to dashboard Cite

show abstract

“…Protein contact networks, perturbation response scanning, softness-based prediction of intersubunits affinity and binding site prediction tools points toward an allosteric modulation region on the spike protein [ 115 – 117 ]. Elastic network model analysis, binding site predictions followed by MD simulations has been used to predict the allosteric sites on the main protease protein [ 118 , 119 ]. The identification of allosteric binding sites on the main protease has also been identified by mass spectrometry based studies [ 120 ].…”

Section: Overview Of Some Of the Applications Of Structural Bioinformmentioning

confidence: 99%

The impact of structural bioinformatics tools and resources on SARS-CoV-2 research and therapeutic strategies

Waman¹,

Sen²,

Váradi³

et al. 2020

Briefings in Bioinformatics

View full text Add to dashboard Cite

SARS-CoV-2 is the causative agent of COVID-19, the ongoing global pandemic. It has posed a worldwide challenge to human health as no effective treatment is currently available to combat the disease. Its severity has led to unprecedented collaborative initiatives for therapeutic solutions against COVID-19. Studies resorting to structure-based drug design for COVID-19 are plethoric and show good promise. Structural biology provides key insights into 3D structures, critical residues/mutations in SARS-CoV-2 proteins, implicated in infectivity, molecular recognition and susceptibility to a broad range of host species. The detailed understanding of viral proteins and their complexes with host receptors and candidate epitope/lead compounds is the key to developing a structure-guided therapeutic design. Since the discovery of SARS-CoV-2, several structures of its proteins have been determined experimentally at an unprecedented speed and deposited in the Protein Data Bank. Further, specialized structural bioinformatics tools and resources have been developed for theoretical models, data on protein dynamics from computer simulations, impact of variants/mutations and molecular therapeutics. Here, we provide an overview of ongoing efforts on developing structural bioinformatics tools and resources for COVID-19 research. We also discuss the impact of these resources and structure-based studies, to understand various aspects of SARS-CoV-2 infection and therapeutic development. These include (i) understanding differences between SARS-CoV-2 and SARS-CoV, leading to increased infectivity of SARS-CoV-2, (ii) deciphering key residues in the SARS-CoV-2 involved in receptor–antibody recognition, (iii) analysis of variants in host proteins that affect host susceptibility to infection and (iv) analyses facilitating structure-based drug and vaccine design against SARS-CoV-2.

show abstract

“…These leads to a conclusion that nsp7 and nsp8 within this complex must carry an RNA binding domain. The NTP entrance channel within the nsp12 (formed by the hydrophilic residues like Lys545, Arg553, Arg555 of Motif F), facilitates the entry of the incoming NTPs [48]. After the initial binding of the template or parental RNA with nsp7, the RNA is expected to meditate its entry into the active site of nsp12 polymerase domain (formed by Motif A & Motif C) and synthesis of new RNA strand takes place [28].…”

Section: Molecular Docking Studiesmentioning

confidence: 99%

In silico analysis of RNA-dependent RNA polymerase of the SARS-CoV-2 and potentiality of the pre-existing drugs

Mukhoty

Ghosh

et al. 2020

Preprint

View full text Add to dashboard Cite

Background: The alarming increase in the number of SARS-CoV-2 cases worldwide, urgently demands far-reaching effective strategies to win the battle against emerging as well as re-emerging diseases. Many research laboratories are conducting clinical trials with different drugs, among which some became quite interestingly effective against this pandemic. Our aim is to investigate the potentiality of the pre-existing drugs and get a clear understanding of their effects on RNA-dependent RNA polymerase (RdRp) of the SARS-CoV-2. Methods: Multiple sequence alignment (MSA) alogwith molecular phylogeny analysis were performed using homologous sequences to identify the mutations within RdRp and evolutionary relationship. Based on the published literatures, we have chosen eight drug molecules like Ribavirin, Tenofovir, Sofosbuvir, IDX-184, YAK, Setrobuvir, Remdesivir and Galidesivir. Series of molecular docking studies between template RNA and RdRp of SARS-CoV-2 has been performed in absence or presence of those drugs and cofactors nsp7 and nsp8.Results: From MSA 13 exclusive mutations identified within RdRp of SARS-CoV-2 and phylogeny reveals its close relation with Bat coronavirus RaTG13. The interaction affinities and interacting residues as obtained from systematic molecular docking study led to a conclusion that the chosen drugs can prove to be effective against this pandemic partially. Conclusion: Therefore, designing of inhibitors which will specifically act against nsp12 and lower the binding affinity of nsp12 towards RNA template is necessary. In this article we additionally focus on the nsp7-8 hexadecameric complex and had suggested a list of amino acid residues of nsp12 and nsp7-8 complex to develop far-reaching effective drugs.

show abstract

A “Deep Dive” into the SARS-Cov-2 Polymerase Assembly: Identifying Novel Allosteric Sites and Analyzing the Hydrogen Bond Networks and Correlated Dynamics

Cited by 7 publications

References 50 publications

Evaluating the effects of SARS-CoV-2 Spike mutation D614G on transmissibility and pathogenicity

Evaluating the effects of SARS-CoV-2 Spike mutation D614G on transmissibility and pathogenicity

The impact of structural bioinformatics tools and resources on SARS-CoV-2 research and therapeutic strategies

In silico analysis of RNA-dependent RNA polymerase of the SARS-CoV-2 and potentiality of the pre-existing drugs

Contact Info

Product

Resources

About