Insight into reactive chemistry is crucial to understanding the mechanism of drug receptor interactions in systems where the ligand is covalently bound to the receptor. For example, it's necessary to study the transition states between bound and unbound forms in order to design antibiotics that are not subject to inactivation by beta lactamases. Classical molecular mechanics (MM) methods cannot describe the electronic changes during a reaction, and are ill-equipped to address ligand-receptor interactions in systems containing metals.
Ab initio quantum mechanics (QM) is required to study reactive chemistry or interactions involving transition metals in a protein environment. However, even with today's computer technology, full QM calculations of entire proteins are still intractable.
Mixed QM/MM calculations provide the ideal solution by separating out the reactive core, which can be accurately described with QM, while treating the remainder of the complex more efficiently with MM. While QM/MM may not be needed for every structure-based drug design project, many important systems cannot be effectively addressed by any other computational means. QM/MM is therefore a key component in the arsenal of computational drug discovery.