In silico comparison of SARS-CoV-2 spike protein-ACE2 binding affinities across species and implications for virus origin

Abstract

The devastating impact of the COVID-19 pandemic caused by SARS–coronavirus 2 (SARS-CoV-2) has raised important questions about its origins and the mechanism of its transfer to humans. A further question was whether companion or commercial animals could act as SARS-CoV-2 vectors, with early data suggesting susceptibility is species specific. To better understand SARS-CoV-2 species susceptibility, we undertook an in silico structural homology modelling, protein–protein docking, and molecular dynamics simulation study of SARS-CoV-2 spike protein’s ability to bind angiotensin converting enzyme 2 (ACE2) from relevant species. Spike protein exhibited the highest binding to human (h)ACE2 of all the species tested, forming the highest number of hydrogen bonds with hACE2. Interestingly, pangolin ACE2 showed the next highest binding affinity despite having a relatively low sequence homology, whereas the affinity of monkey ACE2 was much lower despite its high sequence similarity to hACE2. These differences highlight the power of a structural versus a sequence-based approach to cross-species analyses. ACE2 species in the upper half of the predicted affinity range (monkey, hamster, dog, ferret, cat) have been shown to be permissive to SARS-CoV-2 infection, supporting a correlation between binding affinity and infection susceptibility. These findings show that the earliest known SARS-CoV-2 isolates were surprisingly well adapted to bind strongly to human ACE2, helping explain its efficient human to human respiratory transmission. This study highlights how in silico structural modelling methods can be used to rapidly generate information on novel viruses to help predict their behaviour and aid in countermeasure development.

SARS-CoV-2 Delta Variant Pathogenesis and Host Response in Syrian Hamsters

“…Animal models have been used to explore various disease aspects of SARS-CoV-2 as well as for establishing the safety and efficacy of many interventional measures [13]. Studies have shown the high binding affinity of SARS-CoV-2 spike protein to hamster ACE2 receptor [14]. The virus replicates to high titre in the respiratory tract of Syrian hamsters and causes pneumonia [15].…”

Digital Twins: From Personalised Medicine to Precision Public Health

“…What digital twin technology can particularly bring to the desired picture is replacing (at least partially) the generally expensive and resource-intensive laboratory experiments with in silico simulations ( Figure 3 ); cf. [ 15 ], which used computer models of the SARS–coronavirus 2 or SARS-CoV-2 spike protein and the angiotensin converting enzyme 2–ACE2 receptors of different human and animal species to conduct an in silico comparison of protein receptor binding affinities across species. Given the intricacy and complex interconnections of the diverse types of systems within the human body, establishing an adequate, complete human digital twin may be far from reality.…”

SARS-CoV-2 B.1.351 (beta) variant shows enhanced infectivity in K18-hACE2 transgenic mice and expanded tropism to wildtype mice compared to B.1 variant

“…Mutations in the spike (S) protein are responsible for these phenotypes by modifying neutralising epitopes and/or increasing the affinity for the human angiotensin converting enzyme 2 (hACE2) receptor (Gan et al, 2021). In addition to enhance the transmissibility between humans, these mutations can also alter the susceptibility of other host species of the virus, therefore broadening the animal reservoir (Conceicao et al, 2020;Liu et al, 2021;Piplani et al, 2021). Also, animals are well-known coronavirus reservoirs (Menachery et al, 2017).…”