Sequential QM/MM methodology

On the other hand, for polar molecules in polar environments, this approach may lead to errors because the actual polarization of the molecule may significantly surpass any modest estimate (e.g., 20%) and the extra polarization may be responsible for important differences in the solute-solvent interaction. Hence, one needs a strategy to account more systematically for the solute polarization. It would be especially interesting to do it in a way to preserve the main advantage of the sequential QM/MM methodology, that is, performing only statistically relevant QM calculations. 

A sequential QM/MM methodology was applied to study the magnetic shielding constants of hydrated pyridine. In this approach, the liquid configuration is generated first by classical MC simulations. After that, a subset of uncorrelated configurations is sampled and submitted to QM calculations. The MC simulations were carried out in the NPT... 

---