Consistently coupled QM/MM calculations started with Warshel and Levitt 1976 work1,2 that considered an entire enzyme-substrate complex in solution and evaluated the catalytic effect of this system. Our subsequent studies paved the way for quantitative modeling of enzymatic reactions and chemical reactions in solutions. These works have developed and refined hybrid quantum/molecular mechanics (QM/MM) methods that covered the many options of multiscale embedding strategies. This included the EVB with its powerful ability to obtain reliable free energy surfaces, the ab initio QM/MM (QM(ai)/MM) that used the EVB as a reference potential in free energy calculations and the frozen DFT (FDFT) and constraint DFT (CDFT) that allow us to represent all the protein on the ab initio level3. Our group is involved in constant refinement and validation of different QM/MM an related approaches