Highly Conserved Homotrimer Cavity Formed by the SARS-CoV-2 Spike Glycoprotein: A Novel Binding Site

Abstract

An important stage in SARS-CoV-2 life cycle is the fusion of spike(S) protein with the ACE2 host-cell receptor. Therefore, to explore conserved features in S protein dynamics and to identify potentially novel regions for drugging, we measured variability derived from 791 viral genomes and studied its properties by MD simulation. The findings indicated that S2 subunit (HR1, CH, and CD domains) showed low variability, low fluctuations in MD, and displayed a trimer cavity. By contrast, the RBD domain, which is typically targeted in drug discovery programmes, exhibits more sequence variability and flexibility. Interpretations from MD suggest that the monomer is in constant motion showing transitions up-to-down state, and the trimer cavity may function as a 'bouncing spring' that may facilitates S protein interactions with ACE2. Feasibility of trimer cavity for potential drug target was examined by SBVS screening. Several hits that have already been validated or suggested to inhibit the SARS-CoV-2 virus in cell systems were identified; in particular, the data suggest an action mechanism for such molecules including Chitosan and macrolide types. These findings identify a novel binding-site formed by the S protein, that might assist in future drug discovery programmes aimed at targeting the CoV family of viruses.

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“…The virus spike's transmembrane-glycoprotein,a homotrimer [9] is responsible for the entry of viral RNA into the host cell. Its S1 subunit attaches to ACE2 receptors of the host cell which stimulates formation of TMPRSS2 (Transmembrane protease Serin-2) [10] .…”

Virtual screening of phytochemical compounds as potential inhibitors against SARS-CoV-2 infection

“…1 ) [ 3 ]. The S1 subunit with the larger receptor binding domain and the S2 subunit which induces the membrane fusion polypeptides forming the six helix bundle which results in complete fusion and insertion of viral genome to the host cell cytosol [ 6 ]. Hence, structural analysis on the S-protein could reveal possible mechanisms by which the viral replication could be terminated/controlled [ 7 ].…”

Coevolution, Dynamics and Allostery Conspire in Shaping Cooperative Binding and Signal Transmission of the SARS-CoV-2 Spike Protein with Human Angiotensin-Converting Enzyme 2

“…The rapidly emerging plethora of computational studies examined SARS-CoV-2-RBD interactions with ACE2 enzyme using the recent crystal structures [ 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 ]. It was proposed that SARS-CoV-2-RBD may have adopted a specific strategy for achieving favorable binding affinity by exploiting the larger binding interface as compared to the SARS-CoV-RBD that employs the fewer contacts and could rely only on major hotpot centers [ 29 ].…”

“…This study demonstrated that the dynamics of glycan shield can be allosterically coupled to conformational changes, regulating the equilibrium transitions and response to the host receptor. MD simulations of the SARS-CoV-2 spike glycoprotein identified the changes in the molecular properties due to conformational flexibility [ 35 ]. Several computational methods were used to identify potential allosteric sites on the SARS-CoV-2 spike protein [ 36 ] and employed network modeling to suggest allosteric signaling as a possible mechanism underlying virus transmission in the SARS-CoV-2 spike proteins [ 37 ].…”