SARS-CoV-2 variants and bebtelovimab: immune escape mechanisms revealed by computational studies.

The receptor binding domain (RBD) of SARS-CoV-2 (coronavirus) targets and facilitates the binding with the human ACE2 receptor and is also a target for most monoclonal antibodies for the inhibition process. The emerging mutations in the RBD of SARS-CoV-2 are problematic, as their local and non-local effects can disrupt the binding mechanism of the antibody with the coronavirus's viral protein, thus compromising the antibody's inhibitory function. In this study, we have employed molecular dynamics to elucidate the binding mechanism between human-derived monoclonal antibody, bebtelovimab, and the RBD of the viral spike protein and the effects of mutations on this binding. We have analyzed the unbinding process using molecular dynamics with enhanced sampling methods, such as umbrella sampling. Our findings revealed that certain residues, including 440(N/K), Lys444, 452(L/R), 484(E/A), 498(Q/R), and THR500, are directly or indirectly responsible for altering the binding position and efficacy of bebtelovimab antibody with the RBD when mutations are introduced. The binding energy studies on three different variants, wild-type, delta, and omicron, revealed that the binding efficacy of bebtelovimab with the RBD diminished over time as additional mutations were introduced.