The results provide insights into the molecular mechanism involved in the initial stage of the SARS-CoV-2 infection. The key interactions contributing to the difference of the activation pathways and free energy landscapes were discussed.
In addition, the conformational equilibrium of the SARS-CoV-2 S-protein is more biased to the inactive state compared to that of the SARS-CoV S-protein, suggesting the transient feature of the active state before binding to the receptor protein of the host cell. The transition from inactive to an active state for the S-protein of SARS-CoV-2 is more cooperative, involving simultaneous disruptions of several key interfacial hydrogen bonds, and the transition encounters a much higher free energy barrier.
Our results revealed a large difference between the activation pathways of the two S-proteins. In this work, we investigated the activation pathways and free energy landscape of the S-protein of SARS-CoV-2 and compared with those of the closely related counterpart SARS-CoV using molecular dynamics simulations. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) uses a spike protein (S-protein) to recognize the receptor protein ACE2 of human cells and initiate infection, during which the conformational transition of the S-protein from inactive (down) state to active (up) state is one of the key molecular events determining the infectivity but the underlying mechanism remains poorly understood.
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