Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been spreading worldwide with dramatic consequences. Its elusive and still much debated proximal origin strongly limits the possibility of foreseeing other spillover events with high-risk pandemic potential. Several related coronaviruses have been identified so far and RaTG13 is currently believed the closest bat ancestor.

However, the wealth of current available evidences is still scarce and does not inform on the evolutionary path SARS-CoV-2 has trailed from bats to humans.

Here, through massive plain MD simulations, enhanced sampling calculations, free energy-based alchemical transformation and bioinformatics we show that SARS-CoV-2 likely evolved in Rhinolophus affinis bats by acquiring a surprisingly-high affinity for their ACE2 receptors.

Our results elucidate the receptor binding mode and host adaption mechanisms of RaTG13 and clarify the nature of the multiple selective pressures spike protein underwent that have caused those key mutations accumulated from RaTG13 to SARS-CoV-2.

Overall, our study emphasizes the need of a continuous surveillance of coronaviruses vehiculated by animal reservoirs to prevent future pandemics.

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Vito Genna, Milosz Wiekzor, Adam Hospital, Modesto Orozco (2022):
Evolutionary Path and Host-selection Mechanism of SARS-CoV-2.