The receptor binding domain of SARS-CoV-2 spike protein is the result of an ancestral recombination between the bat-CoV RaTG13 and the pangolin-CoV MP789

Flores-Alanis, Alejandro; Sandner-Miranda, Luisa; Delgado, Gabriela; Cravioto, Alejandro; Morales-Espinosa, Rosario

doi:10.1186/s13104-020-05242-8

Cited by 40 publications

(45 citation statements)

References 40 publications

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“…Analysis of the alignment using the ConSurf server 51 indicates that most residues of the spike protein are highly conserved. In agreement with previous studies, 18,52 the variable residues are primarily concentrated in the receptor binding domain (Fig. 5).…”

Section: Resultssupporting

confidence: 93%

Distant Residues Modulate Conformational Opening in SARS-CoV-2 Spike Protein

Ray

Andricioaei

2020

Preprint

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Infection by SARS-CoV-2 involves the attachment of the receptor binding domain (RBD) of its spike proteins to the ACE2 receptors on the peripheral membrane of host cells. Binding is initiated by a down to up conformational change in the spike protein, an opening which presents the RBD to the receptor. To date, computational and experimental studies for therapeutics have concentrated, for good reason, on the RBD. However, the RBD region is highly prone to mutations, and therefore will possibly arise drug resistance. In contrast, we here focus on the correlations between the RBD and residues distant to it in the spike protein. We thereby provide a deeper understanding of the role of distant residues in the molecular mechanism of infection. Predictions of key mutations in distant allosteric binding sites are provided, with implications for therapeutics. Identifying these emerging mutants can also go a long way towards pre-designing vaccines for future outbreaks. The model we use, based on time-independent component analysis (tICA) and protein graph connectivity network, is able to identify multiple residues that exhibit long-distance coupling with the RBD opening. Mutation on these residues can lead to new strains of coronavirus with different degrees of transmissibility and virulence. The most ubiquitous D614G mutation and the A570D mutation of the highly contagious UK SARS-CoV-2 variant are predicted ab-initio from our model. Conversely, broad spectrum therapeutics like drugs and monoclonal antibodies can be generated targeting these key distant but conserved regions of the spike protein.Significance statementThe novel coronavirus (SARS-CoV-2) pandemic resulted in the largest economic and public health crises in recent times. Significant drug design effort, against SARS-CoV-2, is focused on the receptor binding domain (RBD) of the spike protein, although this region is prone to mutations causing therapeutic resistance. We applied deep data analysis methods on all-atom molecular dynamics simulations to identify key non-RBD residues that play a crucial role in spike-receptor binding and infection. Because the non-RBD residues are typically conserved across multiple coronaviruses, they can not only be targeted by broad spectrum antibodies and drugs against existing strains, but can also offer predictive insights into how to design adaptable antiviral therapeutic framework against spike of strains that might appear during future epidemics.

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Section: Resultssupporting

confidence: 93%

Distant Residues Modulate Conformational Opening in SARS-CoV-2 Spike Protein

Ray

Andricioaei

2020

Preprint

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“…Lack of a significant regression of linkage disequilibrium with distance between loci argues for a rarity of recombination events, not for their absence. Recombination is clearly an important aspect of coronavirus evolution [13][14][15][16] , which has been shown to play a role in the origins of SARS-CoV-2 15,17,18 and SARS-CoV-1 19 . More directly relevant, several studies have found occurrences of recombination among SARS-CoV-2 variants [20][21][22][23] .…”

Section: Recombinationmentioning

confidence: 99%

Recombination and low-diversity confound homoplasy-based methods to detect the effect of SARS-CoV-2 mutations on viral transmissibility

Giorgi

Bhattacharya

Fischer

et al. 2021

Preprint

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The SARS-CoV-2 variant carrying the Spike protein mutation G614 was first detected in late January 2020 and within a few months became the dominant form globally. In the months that followed, many studies, both in vitro and in animal models, showed that variants carrying this mutation were more infectious and more readily transmitted than the ancestral Wuhan form. Here we investigate why a recently published study by van Dorp et al. failed to detect such higher transmissibility of the G614 variant using homoplasy-based methods. We show that both low diversity and recombination confound the methods utilized by van Dorp et al. and significantly decrease their sensitivity. Furthermore, though they claim no evidence of recombination in their dataset, we and several other studies identify a subset of the sequences as recombinants, possibly enough to affect their statistic adversely.

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“…Malayan pangolins (Manis javanica) have been the subject of some speculation on the basis of infection with a closely related coronavirus in animals seized in southern China [16]. Sequence analysis of the spike glycoprotein (S) of SARS-CoV-2 and related coronaviruses suggest a series of recombination events between bat and pangolin coronaviruses, eventually leading to the emergence of this novel coronavirus [17]. However, raccoon dogs (Nyctereutes procyonoides), which were identified as possible intermediate hosts for the SARS pandemic of 2002-2003 [18], have also been suggested as candidate intermediate hosts for SARS-CoV-2 as experimental infection resulted in intense viral shedding [19].…”

Section: Wildlife Origins Of Sars-cov-2mentioning

confidence: 99%

“…Another reason is that none of the previous zoonotic coronaviruses have achieved the same rapid, efficient, and large scale spread within the human population sufficient to support widespread spillover and cross species jumping. Consequently, molecular epidemiological surveillance will be required across this host range, using viral isolates obtained from different animal species and identifying the genetic changes and novel adaptations linked to cross -species transmission [17].…”

Section: Surveillance and Dynamic Risk Assessmentmentioning

confidence: 99%

Assessing the Risks of SARS-CoV-2 in Wildlife

Delahay¹,

Fuente²,

Smith³

et al. 2020

Preprint

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The novel coronavirus SARS-CoV-2 likely emerged from a wildlife source with transmission to humans followed by rapid geographic spread throughout the globe and dramatic impacts on both human health and global economies. Since the onset of the pandemic, there have been several instances of human-to-animal transmission involving companion, farmed and zoo animals, with the clear potential for spread into free-living wildlife. The establishment of reservoirs of infection in wild animals would create significant challenges to infection control in humans and could pose a threat to the welfare and conservation status of wildlife. Herein, we discuss the potential for exposure, maintenance and onward transmission of SARS-CoV-2 in an initial selection of wild and feral species (bats, canids, felids, mustelids, great apes). Targeted surveillance and dynamic risk assessment are important tools for the early detection of infection in wildlife and a means of collating and synthesising emerging information in a rapidly changing situation. Such efforts should be integrated with public health information to provide insights into the potential role of wild mammals in the continuing epidemiology of SARS-CoV-2. This approach should also be adopted to address the wider need to proactively assess threats to human and animal health from other diseases that may emerge from wildlife.

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The receptor binding domain of SARS-CoV-2 spike protein is the result of an ancestral recombination between the bat-CoV RaTG13 and the pangolin-CoV MP789

Cited by 40 publications

References 40 publications

Distant Residues Modulate Conformational Opening in SARS-CoV-2 Spike Protein

Distant Residues Modulate Conformational Opening in SARS-CoV-2 Spike Protein

Recombination and low-diversity confound homoplasy-based methods to detect the effect of SARS-CoV-2 mutations on viral transmissibility

Assessing the Risks of SARS-CoV-2 in Wildlife

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