Neuropilin-1 Assists SARS-CoV-2 Infection by Stimulating the Separation of Spike Protein Domains S1 and S2

Zhen-lu, Li; Matthias, Buck

The cell surface receptor Neuropilin-1 (Nrp1) was recently identified as a host factor for SARS-CoV-2 entry. Spike protein of SARS-CoV-2 is cleaved into two segments, the S1 (res. 1-685) and the S2 (res. 686-1273) domain by furin protease. Nrp1 predominantly binds to the C-terminal RRAR motif (res. 682-685) of the S1 domain. In this study, we firstly modeled the association of a Nrp1 protein (consisting of domains a2-b1-b2) with the Spike protein. Next, we studied the separation of S2 from the S1 domain, with and without Nrp1 bound, by utilizing molecular dynamics pulling simulations. During the separation, Nrp1 stabilizes the S1 C-terminal region (res. 640-685) and thereby assists the detachment of S2 N-terminal region (res. 686-700). Without Nrp1 bound, S1 tends to become stretched and thus the bound Nrp1 stimulates the earlier separation of S2 from the S1 domain. The liberated S2 domain is known to mediate the fusion of virus and host membranes, thus Nrp1 likely increases virus infectivity by facilitating the S1/S2 separation. We further analyzed the possible topological structure of the SARS-CoV-2 Spike protein when bound with Nrp1 and ACE2. Understanding of such a Nrp1-assisted viral infection opens the gate for the generation of protein-protein inhibitors, such as antibodies, which could attenuate the infection mechanism and protect certain cells in a future Nrp1:ACE2 targeted combination therapy.