A key advantage of our optimized GFN2-xTB parametrizations is their computational efficiency, which enables extended sampling in QM/MM simulations. While reference DFT calculations were limited to 1 picosecond of sampling per reaction coordinate window, our optimized parameters allowed for much longer sampling windows. This extended sampling capability provides more thorough exploration of conformational space, potentially leading to more accurate free energy profiles. This algorithm can be applied to any combination of semiempirical and DFT/ab initio level.