Integrated framework for targeting dynamic penicillin-binding protein 2a via ensemble structural biology and deep generative modeling

Methicillin-resistant Staphylococcus aureus (MRSA) remains a major cause of morbidity and mortality worldwide, largely due to penicillin-binding protein 2a (PBP2A), a low-affinity transpeptidase encoded by mecA. To address the challenge of this highly flexible target, we developed an integrated discovery framework combining conformational ensemble analysis with deep generative modeling. Extensive molecular dynamics simulations were used to map the dynamic landscape of PBP2A and identify cryptic