The entry of the SARS-CoV-2, a causative agent of COVID-19, into human host cells is mediated by the SARS-CoV-2 spike (S) glycoprotein, which critically depends on the formation of complexes involving the spike protein receptor-binding domain (RBD) and the human cellular membrane receptor angiotensin-converting enzyme 2 (hACE2). Using classical site density functional theory (SDFT) and structural bioinformatics methods, we investigate binding and conformational properties of these complexes and study the overlooked role of water-mediated interactions. Analysis of the three-dimensional reference interaction site model (3DRISM) of SDFT indicates that water mediated interactions in the form of additional water bridges strongly increases the binding between SARS-CoV-2 spike protein and hACE2 compared to SARS-CoV-1-hACE2 complex. By analyzing structures of SARS-CoV-2 and SARS-CoV-1, we find that the homotrimer SARS-CoV-2 S receptor-binding domain (RBD) has expanded in size, indicating large conformational change relative to SARS-CoV-1 S protein. Protomer with the up-conformational form of RBD, which binds with hACE2, exhibits stronger intermolecular interactions at the RBD-ACE2 interface, with differential distributions and the inclusion of specific H-bonds in the CoV-2 complex. Further interface analysis has shown that interfacial water promotes and stabilizes the formation of CoV-2/hACE2 complex. This interaction causes a significant structural rigidification of the spike protein, favoring proteolytic processing of the S protein for the fusion of the viral and cellular membrane. Moreover, conformational dynamics simulations of RBD motions in SARS-CoV-2 and SARS-CoV-1 point to the role in modification of the RBD dynamics and their impact on infectivity.
A new coronavirus epidemic COVID-19 caused by Severe Acute Respiratory Syndrome coronavirus (SARS-CoV-2) poses serious threat across continents, leading to the World Health Organization declaration of a Public Health Emergence of International Concern. In order to stop the entry of the virus into human host cell, major therapeutic and vaccine design efforts are now targeting interactions between the SARS-CoV-2 spike (S) glycoprotein and the human cellular membrane receptor angiotensin-converting enzyme, hACE2. By analysing cryo-EM structures of SARS-CoV-2 and SARS-CoV-1, we report here that the homotrimer SARS-CoV-2 S receptor-binding domain (RBD) that bind with hACE2 has expanded in size with a large conformational change of its AA residues relative to SARS-CoV-1 S protein. Protomer with the up-conformational form RBD that only can bind with hACE2 showed higher intermolecular interactions at the interface, with differential distributions and the inclusion of two specific H-bonds in the CoV-2 complex. However, these interactions are resulted in significant reductions in structural rigidity, favouring proteolytic processing of S protein for the fusion of the viral and cellular membrane. Further conformational dynamics analysis of the RBD motions of SARS-CoV-2 and SARS-CoV-1 point to the role in modification in the RBD conformational dynamics and their likely impact on infectivity.
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