The emergence of Omicron SARS-CoV-2 subvariants (BA.1, BA.2, BA.4, and BA.5) with an unprecedented number of mutations in their receptor-binding domain (RBD) of the spike-protein has fueled a new surge of COVID-19 infections, posing a major challenge to the efficacy of existing vaccines and monoclonal antibody (mAb) therapeutics. Here, a thorough and systematic molecular dynamics (MD) simulation study is conducted to investigate how the RBD mutations on these subvariants affect the interactions

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... with broad mAbs including AstraZeneca (COV2-2196 and COV2-2130), Brii Biosciences (BRII-196), Celltrion (CT-P59), Eli Lilly (LY-CoV555 and LY-CoV016), Regeneron (REGN10933 and REGN10987), Vir Biotechnology (S309), and S2X259. Our results show a complete loss of binding for COV2-2196, BRII-196, CT-P59, and LY-CoV555 with all Omicron RBDs. REGN10987 also loses its binding against BA.1 but partially retains against BA.2 and BA.4/5. The reduction in binding is either significant for LY-CoV016 and REGN10933 or moderate for COV2-2130. S309 and S2X259 retain their binding strength against BA.1 but decrease against others. We introduce a mutational escape map for each mAb to identify the key RBD sites and critical mutation. Overall, our findings suggest that majority of therapeutic mAbs have diminished or lost their activity against Omicron subvariants, indicating the urgent need for a new therapeutic mAb, modifying current ones with a better mAb design, or seeking an alternative approach.