Warning: This is a preliminary report that has not been peer-reviewed. It should not be regarded as conclusive, guide clinical practice/health-related behavior, or be reported in news media as established information.

Sergeeva AP, Katsamba PS, Sampson JM, Bahna F, Mannepalli S, Morano NC, Shapiro L, Friesner RA, Honig B

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 ...

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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.SignificanceThe ability to accurately predict binding affinity changes upon mutations of interfacial residues is a problem of significant importance, ranging from the understanding of interaction specificity to the design of therapeutics such as potent monoclonal antibodies that target antigens. Here we report on the ability of various computational methods to predict the effects of SARS-CoV-2 receptor binding domain (RBD) mutations on binding its host receptor (ACE2). We find that free energy perturbation (FEP) calculations are particularly effective. Moreover, analysis of FEP trajectories provides physical insights that may be useful in developing strategies for binding affinity optimization of therapeutic antibodies. Our results suggest that FEP calculations can predict epistatic effects that are likely to be an important component of antibody design.

Date: Aug. 01, 2022

Status: Preliminary Report

View Source: doi: 10.1101/2022.08.01.502301

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