Determination of enzymatic reaction pathways using QM/MM methods

Enzymes are among the most powerful known catalysts. Understanding the functions of these proteins is one of the central goals of contemporary chemistry and biochemistry. But, because these systems are large they are difficult to handle using standard theoretical chemistry tools. In the last 10 years, we have seen the rapid development of so‐called QM/MM methods that combined quantum chemistry and molecular mechanics to elucidate the structure and functions of systems with many degrees of freedom, including enzymatic systems. In this article, we review the numerical aspects of QM/MM methods applied to enzymes: The energy definition, the special treatment of the covalent QM/MM frontiers, and the exploration of QM/MM potential energy surface. A special emphasis is made on the use of local self‐consistent field and rational function optimization.