Here, we have used multiscale simulations to model the rate-limiting first step of the carbapenem deacylation reaction for a panel of class A beta-lactamases that differ in activity towards these important antibiotics. The QM/MM simulations correctly discriminate between carbapenemases and enzymes that are inhibited by carbapenems. The results help explain why some class A lactamases readily hydrolyze carbapenem antibiotics, whereas other very similar enzymes do not.