In that work, meropenem breakdown efficiency is correctly captured using Glu166 as the general base for the deacylation reaction. Here, we use a similar approach in a detailed computational investigation into the origins of the differences in activity between the two groups of enzymes. We compare the carbapenemases KPC-2, SFC-1, SME-1 and NMC-A with the carbapenem-inhibited BlaC, TEM-1, SHV-1 and CTX-M-16 class A β-lactamases. We extend our simulations to several variants (including SFC-1 Asn132Gly, BlaC Gly132Asn and SFC-1 Cys238Gly) to investigate the influence of specific interactions on deacylation activity. Establishing how the subtle differences between enzymes able to destroy carbapenems and those that cannot affect interactions with and turnover of carbapenems may guide design of new β-lactam antibiotics that are more resistant to breakdown by currently circulating β-lactamase enzymes.