  Heparin is administered intravenously as an anticoagulant to COVID-19
patients and via aerosol to treat other lung diseases. It has recently been
found to have antiviral activity against SARS-CoV-2 as it hinders attachment of
the virus to the host cell by binding to the virus spike glycoprotein. Here, we
describe molecular dynamics simulations to investigate how heparin binds to the
spike and the mechanism by which it exerts its antiviral activity. The
simulations show that heparin polyanionic chains can bind at long, mostly
positively charged patches on the spike, preventing the binding of host cell
heparan sulphate proteoglycans to the spike. Heparin can mask both the S1/S2
basic motif, thereby inhibiting furin cleavage and the formation of the
prefusion conformation, and the basic residues of the receptor binding domain
(RBD), thus acting on the hinge region responsible for the motion of the RBD
between inactive closed and active open conformations of the spike. In
simulations of the closed spike, heparin binds the RBD and the N-terminal
domain of two adjacent spike subunits and hinders the opening. In simulations
of the open spike, heparin binds similarly but induces stabilization of the
hinge region and a change in RBD motion. Heparin is therefore able to inhibit
host cell attachment directly and by two allosteric mechanisms. Furthermore,
the simulations provide insights into how heparan sulphate proteoglycans on the
host cell can facilitate viral infection. Our results will aid the rational
optimization of heparin derivatives for SARS-CoV-2 antiviral therapy.
