Entropic Overcompensation of the N501Y Mutation on SARS-CoV-2 S Binding to ACE2

Abstract

Recent experimental work has shown that the N501Y mutation in the SARS-CoV-2 S glycoprotein’s receptor binding domain (RBD) increases binding affinity to the angiotensin-converting enzyme 2 (ACE2), primarily by overcompensating for a less favorable enthalpy of binding by greatly reducing the entropic penalty for complex formation, but the basis for this entropic overcompensation is not clear [J. Biol. Chem.2021297101151]. We use all-atom molecular dynamics simulations and free-energy calculations to qualitatively assess the impact of the N501Y mutation on the enthalpy and entropy of binding of RBD to ACE2. Our calculations correctly predict that N501Y causes a less favorable enthalpy of binding to ACE2 relative to the original strain. Furthermore, we show that this is overcompensated for by a more entropically favorable increase in large-scale quaternary flexibility and intraprotein root mean square fluctuations of residue positions upon binding in both RBD and ACE2. The enhanced quaternary flexibility stems from N501Y’s ability to remodel the inter-residue interactions between the two proteins away from interactions central to the epitope and toward more peripheral interactions. These findings suggest that an important factor in determining protein–protein binding affinity is the degree to which fluctuations are distributed throughout the complex and that residue mutations that may seem to result in weaker interactions than their wild-type counterparts may yet result in increased binding affinity thanks to their ability to suppress unfavorable entropy changes upon binding.

Effect of computationally designed fragment-based analogs on the RBD–ACE2 complex of the SARS-CoV-2 P.1 variant

“…The binding strength is associated with the degree of fluctuation distributed throughout the complex. 60 In an MDS study reported by Vergara et al, 60 N501Y mutation provides an enhanced quaternary flexibility responsible for remodeling the interresidue interactions between RBD-ACE2 and contributes towards better interaction. Surprisingly, we observed an overall gain in interface contacts and more negative binding energy between the RBD and ACE2 in compound-bound complexes (Fig.…”