How Accurate Are QM/MM Models?

Abstract

Despite the success and widespread use of QM/MM methods in modeling (bio)chemically important processes, their accuracy is still not well understood. A key reason is because these methods are ultimately approximations to direct QM calculations of very large systems, which are impractical to perform in most cases. We highlight recent progress toward the development of realistic model systems where it is possible to obtain full QM reference data to directly and systematically evaluate the effectiveness of different QM/MM generation schemes. These model systems are highly flexible and can be tailored to probe the sensitivity of a QM/MM model to different reaction types and simulation parameters such as pairing of QM and MM potentials, QM region size, and composition. It is envisaged that this strategy could be used to directly validate different QM/MM generation schemes and spur the development of more robust models in the future.