Reduction of RBD Binding Affinity to Glycosylated ACE2 is Entropic in Origin
The spike protein in the virus SARS-CoV-2 (the causative agent of COVID-19) recognizes the host cell by binding to the peptidase domain (PD) of the extracellular enzyme Angiotensin-converting Enzyme 2 (ACE2). A variety of carbohydrates could be attached to the six asparagines in the PD, resulting in a heterogeneous population of ACE2 glycoforms. Experiments have shown that the binding affinity of glycosylated and deglycosylated ACE2 to the virus is virtually identical. In most cases, the reduction in glycan size correlates with stronger binding, which suggests that volume exclusion, and hence entropic forces, determine the binding affinity. Here, we quantitatively test the entropy-based hypothesis by developing a lattice model for the complex between ACE2 and the SARS-CoV-2 spike protein Receptor-binding Domain (RBD). Glycans are treated as branched polymers with only volume exclusion, which we justify using all atom molecular dynamics simulations in explicit water. We show that the experimentally measured changes in the ACE2-RBD dissociation constants for a variety of engineered ACE2 glycoforms are well accounted for by our theory, thus affirming that ACE2 glycans have only a weak, entropic effect on RBD binding.