  Due to the low density of envelope (Env) spikes on the surface of HIV-1,
neutralizing IgG antibodies rarely bind bivalently using both antigen-binding
arms (Fabs) to crosslink between spikes (inter-spike crosslinking), instead
resorting to weaker monovalent binding that is more sensitive to Env mutations.
Synthetic antibodies designed to bivalently bind a single Env trimer
(intra-spike crosslinking) were previously shown to exhibit increased
neutralization potencies. In initial work, diFabs joined by varying lengths of
rigid double-stranded DNA (dsDNA) were considered. Anticipating future
experiments to improve synthetic antibodies, we investigate whether linkers
with different rigidities could enhance diFab potency by modeling DNA-Fabs
containing different combinations of rigid dsDNA and flexible single-stranded
DNA (ssDNA) and characterizing their neutralization potential. Model
predictions suggest that while a long flexible polymer may be capable of
bivalent binding, it exhibits weak neutralization due to the large loss in
entropic degrees of freedom when both Fabs are bound. In contrast, the
strongest neutralization potencies are predicted to require a rigid linker that
optimally spans the distance between two Fab binding sites on an Env trimer,
and avidity can be further boosted by incorporating more Fabs into these
constructs. These results inform the design of multivalent anti-HIV-1
therapeutics that utilize avidity effects to remain potent against HIV-1 in the
face of the rapid mutation of Env spikes.
