Combined quantum mechanics and molecular mechanics (QM/MM) simulations have become an essential methodology for studying biocatalysis and other other quantum-influenced biological processes. Despite the widespread success of these techniques, as underscored by the 2013 Nobel Prize in Chemistry, key challenges remain, particularly when applied to complex biomolecular systems.
In this talk, I will outline several critical issues that influence the reliability and predictive power of QM/MM methods across a broad range of biomolecular systems. These challenges will be illustrated through insights and recent advancements from our recent work. Ongoing efforts by the community continue to enhance the robustness and applicability of QM/MM simulations. These developments enable more accurate descriptions of biomolecular function and reactivity, and supporting molecular engineering efforts. Finally, I will discuss emerging opportunities permitted by these advances, including the application to more challenging problems where quantum effects play a central role.