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Literature detail

Identifying the Zoonotic Origin of SARS-CoV-2 by Modeling the Binding Affinity between the Spike Receptor-Binding Domain and Host ACE2.

Xiaoqiang Huang Chengxin Zhang Robin Pearce Gilbert S Omenn Yang Zhang
PMID 33175551 2020 J Proteome Res eng ppublish
PubMed DOI Browse context

Article

Publication summary

Despite considerable research progress on SARS-CoV-2, the direct zoonotic origin (intermediate host) of the virus remains ambiguous. The most definitive approach to identify the intermediate host would be the detection of SARS-CoV-2-like coronaviruses in wild animals. However, due to the high number of animal species, it is not feasible to screen all the species in the laboratory. Given that binding to ACE2 proteins is the first step for the coronaviruses to invade host cells, we propose a computational pipeline to identify potential intermediate hosts of SARS-CoV-2 by modeling the binding affinity between the Spike receptor-binding domain (RBD) and host ACE2. Using this pipeline, we systematically examined 285 ACE2 variants from mammals, birds, fish, reptiles, and amphibians, and found that the binding energies calculated for the modeled Spike-RBD/ACE2 complex structures correlated closely with the effectiveness of animal infection as determined by multiple experimental data sets. Built on the optimized binding affinity cutoff, we suggest a set of 96 mammals, including 48 experimentally investigated ones, which are permissive to SARS-CoV-2, with candidates from primates, rodents, and carnivores at the highest risk of infection. Overall, this work not only suggests a limited range of potential intermediate SARS-CoV-2 hosts for further experimental investigation, but also, more importantly, it proposes a new structure-based approach to general zoonotic origin and susceptibility analyses that are critical for human infectious disease control and wildlife protection.

binding affinity EvoEF2 energy unit intermediate host SARS-CoV-2 zoonotic origin Angiotensin-Converting Enzyme 2 Animals Binding Sites COVID-19 Host-Pathogen Interactions Humans Mammals Pandemics Protein Binding Protein Domains SARS-CoV-2 Spike Glycoprotein, Coronavirus Viral Zoonoses

Structured evidence records

Evidence records

4 total
Genomic Evolution 1 records
Genomic Evolution Extraction confidence 0.60
Key finding

Computational modeling of the SARS-CoV-2 Spike receptor-binding domain and host ACE2 variants revealed molecular affinity patterns that correlate with cross-species infection likelihood, informing zoonotic origin hypotheses.

Virus
SARS-CoV-2
Host
Mammalia
Location
Not specified
Supporting text

We propose a computational pipeline to identify potential intermediate hosts of SARS-CoV-2 by modeling the binding affinity between the Spike receptor-binding domain (RBD) and host ACE2. Using this pipeline, we systematically examined 285 ACE2 variants from mammals, birds, fish, reptiles, and amphibians, and found that the binding energies calculated for the modeled Spike-RBD/ACE2 complex structures correlated closely with the effectiveness of animal infection as determined by multiple experimental data sets.

Genes or proteins
Spike receptor-binding domain; ACE2
Analysis methods
computational modeling; structure-based analysis
Host Range Experiment 1 records
Host Range Experiment Extraction confidence 0.80
Key finding

Modeling of the SARS-CoV-2 Spike-RBD and ACE2 interactions across 285 animal ACE2 variants indicated binding affinities correlated with known experimental infection data, highlighting mammals—particularly primates, rodents, and carnivores—as likely susceptible hosts.

Virus
SARS-CoV-2
Location
Not specified
Supporting text

We propose a computational pipeline to identify potential intermediate hosts of SARS-CoV-2 by modeling the binding affinity between the Spike receptor-binding domain (RBD) and host ACE2. Using this pipeline, we systematically examined 285 ACE2 variants from mammals, birds, fish, reptiles, and amphibians, and found that the binding energies calculated for the modeled Spike-RBD/ACE2 complex structures correlated closely with the effectiveness of animal infection as determined by multiple experimental data sets.

Method
binding affinity modeling; ACE2 sequence analysis; structure-based host susceptibility prediction
Experimental system
computational modeling of receptor-binding interactions
Molecular Adaptation 1 records
Molecular Adaptation Extraction confidence 0.75
Key finding

SARS-CoV-2 spike receptor-binding domain shows varying binding affinities to ACE2 from diverse vertebrates, suggesting molecular adaptation of spike-mediated receptor binding that influences host susceptibility.

Virus
SARS-CoV-2
Host
Not specified
Location
Not specified
Supporting text

We propose a computational pipeline to identify potential intermediate hosts of SARS-CoV-2 by modeling the binding affinity between the Spike receptor-binding domain (RBD) and host ACE2. Using this pipeline, we systematically examined 285 ACE2 variants from mammals, birds, fish, reptiles, and amphibians, and found that the binding energies calculated for the modeled Spike-RBD/ACE2 complex structures correlated closely with the effectiveness of animal infection.

Genes or proteins
Spike; receptor-binding domain; ACE2
Receptors
ACE2
Mechanism types
receptor_binding; cell_entry; host_factor_interaction
Receptor Usage 1 records
Receptor Usage Extraction confidence 0.95
Key finding

SARS-CoV-2 Spike receptor-binding domain binds to ACE2 proteins from diverse animals, with modeled binding affinity correlated to known infection effectiveness.

Virus
SARS-CoV-2
Location
Not specified
Supporting text

Given that binding to ACE2 proteins is the first step for the coronaviruses to invade host cells, we propose a computational pipeline to identify potential intermediate hosts of SARS-CoV-2 by modeling the binding affinity between the Spike receptor-binding domain (RBD) and host ACE2.

Method
computational modeling; binding affinity modeling
Receptors
ACE2