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ACE2-Variants Indicate Potential SARS-CoV-2-Susceptibility in Animals: A Molecular Dynamics Study.

ABSTRACT: Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) continues to be a global threat, causing millions of deaths worldwide. SARS-CoV-2 is an enveloped virus with spike (S) glycoproteins conferring binding to the host cell's angiotensin-converting enzyme 2 (ACE2), which is critical for cellular entry. The host range of the virus extends well beyond humans and non-human primates. Natural and experimental infections have confirmed the high susceptibility of cats, ferrets, and Syrian hamsters, whereas dogs, mice, rats, pigs, and chickens are refractory to SARS-CoV-2 infection. To investigate the underlying reason for the variable susceptibility observed in different species, we have developed molecular descriptors to efficiently analyse dynamic simulation models of complexes between SARS-CoV-2 S and ACE2. Our extensive analyses represent the first systematic structure-based approach that allows predictions of species susceptibility to SARS-CoV-2 infection.

SUBMITTER: Pach S

PROVIDER: S-EPMC8420607 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has killed over 6 million people and is having a devastating social and economic impact around the world. The rise of new variants of concern (VOCs) represents a difficult challenge due to the loss of vaccine and natural immunity, as well as increased transmissibility. All VOCs contain mutations in the spike glycoprotein, which mediates fusion between the viral and host cell membranes. The spike glycoprotein binds to angiotensin-converting enzyme 2 (ACE2) via its receptor binding domain (RBD) initiating the infection process. Attempting to understand the effect of RBD mutations in VOCs, a lot of attention has been given to the RBD-ACE2 interaction. However, this type of analysis ignores more indirect effects, such as the conformational dynamics of the RBD itself. Observing that some mutations occur in residues that are not in direct contact with ACE2, we hypothesized that they could affect the RBD conformational dynamics. To test this, we performed long atomistic (AA) molecular dynamics (MD) simulations to investigate the structural dynamics of wt RBD, and that of four VOCs (Alpha, Beta, Delta, and Omicron). Our results show that the wt RBD presents two distinct conformations: an "open" conformation where it is free to bind ACE2; and a "closed" conformation, where the RBM ridge blocks the binding surface. The Alpha and Beta variants shift the open/closed equilibrium towards the open conformation by roughly 20%, likely increasing ACE2 binding affinity. Simulations of the Delta and Omicron variants showed extreme results, with the closed conformation being rarely observed. The Delta variant also differed substantially from the other variants, alternating between the open conformation and an alternative "reversed" one, with a significantly changed orientation of the RBM ridge. This alternate conformation could provide a fitness advantage due to increased availability for ACE2 binding, and by aiding antibody escape through epitope occlusion. These results support the hypothesis that VOCs, and particularly the Omicron and Delta variants, impact RBD conformational dynamics in a direction that promotes efficient binding to ACE2 and, in the case of Delta, may assist antibody escape.

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ACE2-Variants Indicate Potential SARS-CoV-2-Susceptibility in Animals: A Molecular Dynamics Study.

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