Free energy perturbation calculations of mutation effects on SARS-CoV-2 RBD::ACE2 binding affinity (preprint)

ABSTRACT

The strength of binding between human angiotensin converting enzyme 2 (ACE2) and the receptor binding domain (RBD) of viral spike protein plays a role in the transmissibility of the SARS-CoV-2 virus. In this study we focus on a subset of RBD mutations that have been frequently observed in sequenced samples from infected individuals and probe binding affinity changes to ACE2 using surface plasmon resonance (SPR) measurements and free energy perturbation (FEP) calculations. We find that FEP performance is significantly better than that of other computational approaches examined here, in part due to its ability to account for protein structure relaxation resulting from the mutation of interfacial residues. Moreover, analysis of FEP trajectories offers physical insights not available from other methods. Notably, FEP calculations successfully predict the observed cooperative stabilization of binding by the Q498R N501Y double mutant present in the Omicron variant and offer a physical explanation for the underlying mechanism. Our results furthermore suggest a strategy as to how to effectively deploy FEP methods in the optimization of neutralizing antibodies.