Structural Insights into the Cofactor Role of Heparin/Heparan Sulfate in Binding between the SARS-CoV-2 Spike Protein and Host Angiotensin-Converting Enzyme II.

The viral entry process of the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) requires heparin and heparan sulfates from the cell surface, functioning as a cofactor for human angiotensin-converting enzyme 2 (ACE2) for recognizing the receptor-binding domain (RBD) of the spike (S) protein on the surface of the virion. In the present study, the binding poses of an oligosaccharide with four repeating units of GlcNS6S-IdoA2S (octa) predicted by Vina-Carb in the RBD binding site were employed in molecular dynamics (MD) simulations to provide atomic details for studying the cofactor mechanism. The molecular model in the MD simulations reproduced the length- and sequence-dependent behavior observed from the microarray experiments and revealed an important planar U-turn shape for HP/HS binding to RBD. The model for octa with this shape in the ACE2-RBD complex enhanced the interactions in the binding interface. The comparisons with the ACE2-RBD complex suggested that the presence of octa in the RBD binding site blocked the movements in a loop region at the distal end of the RBD binding interface and promoted the contacts of this loop region with the ACE2 N-terminus helix. This study shed light on the atomic and dynamic details for HP/HS interacting with RBD and provided insights into their cofactor role in the ACE2-RBD interactions.