Oligomerization-driven avidity correlates with SARS-CoV-2 cellular binding and inhibition.

Cellular processes are controlled by the thermodynamics of the underlying biomolecular interactions. Frequently, structural investigations use one monomeric binding partner, while ensemble measurements of binding affinities generally yield one affinity representative of a 1:1 interaction, despite the majority of the proteome consisting of oligomeric proteins. For example, viral entry and inhibition in SARS-CoV-2 involve a trimeric spike surface protein, a dimeric angiotensin-converting enzyme 2 (ACE2) cell-surface receptor and dimeric antibodies. Here, we reveal that cooperativity correlates with infectivity and inhibition as opposed to 1:1 binding strength. We show that ACE2 oligomerizes spike more strongly for more infectious variants, while exhibiting weaker 1:1 affinity. Furthermore, we find that antibodies use induced oligomerization both as a primary inhibition mechanism and to enhance the effects of receptor-site blocking. Our results suggest that naive affinity measurements are poor predictors of potency, and introduce an antibody-based inhibition mechanism for oligomeric targets. More generally, they point toward a much broader role of induced oligomerization in controlling biomolecular interactions.
Competing Interests: Competing interests statement:P.K. is a nonexecutive director, shareholder of and consultant to Refeyn Ltd., J.L.P.B. and W.B.S. are shareholders of and consultants to Refeyn Ltd. W.B.S. and P.K. received the University of Oxford’s COVID-19 Research Response Fund. P.K. has filed a patent for the contrast enhancement methodology and its application to mass measurement of single biomolecules. G.R.S. is on the GSK Vaccines Scientific Advisory Board, a founder shareholder of RQ biotechnology and Jenner investigator. Oxford University holds intellectual property related to the Oxford-AstraZeneca vaccine.