QM/MM: What have we learned, where are we, and where do we go from here?

This paper briefly reviews the current status of the most popular methods for combined quantum mechanical/molecular mechanical (QM/MM) calculations, including their advantages and disadvantages. There is a special emphasis on very general link-atom methods and various ways to treat the charge near the boundary. Mechanical and electric embedding are contrasted. We consider methods applicable to gas-phase organic chemistry, liquid-phase organic and organometallic chemistry, biochemistry, and solid-state chemistry. Then we review some recent tests of QM/MM methods and summarize what we learn about QM/MM from these studies. We also discuss some available software. Finally, we present a few comments about future directions of research in this exciting area, where we focus on more intimate blends of QM with MM.