The emergence of Klebsiella pneumoniae carbapenemase (KPC) -33, a D179Y variant of KPC-2, confers resistance to the combination of ceftazidime-avibactam (CAZ-AVI), but its atomic-level resistance mechanism remains unclear. To clarify conformational dynamics and substrate selectivity, we conducted extensive molecular dynamics simulations: 6μs equilibrium molecular dynamics simulations (MDs) for apo-enzymes of KPC-2 and KPC-33, 40μs free-binding MDs for enzymes and its substrates, and adaptive steered MD (ASMD), together with the interaction fingerprint and binding free energy analyses. KPC-33 exhibited greater conformational heterogeneity, especially in the Ω-loop region. Free-binding MD simulations showed that the thiazole ring of CAZ wedges into the interface between the Ω-loop and H6 of KPC-33, producing an induced-fit pre-catalytic binding configuration 4 (PCBC-4) that is absent in the simulations for CAZ-KPC-2 and is not reported previously. Binding free energy analysis showed that KPC-33 has higher affinity for CAZ but lower affinity for AVI due to residue-specific energy re-distributions. ASMD suggested that a lower barrier for Ω-loop-H6 separation in KPC-33 than in KPC-2, facilitating PCBC-4 formation. Dynamic network analysis further revealed tighter β-sheet/α-helix coupling in KPC-33, decreased modularity of the SXXK motif and Ω-loop communities. Together, these findings explain how D179Y substitution reshapes KPC-33's conformational landscape, favoring CAZ accommodation while evading avibactam inhibition. This study highlights the Ω-loop-H6 interface as a potential target to restore CAZ-AVI efficacy against resistant β-lactamases.