In recent years, quantum mechanics/molecular mechanics (QM/MM) methods have become an important computational tool for the study of chemical reactions and other processes in biomolecular systems. Because of the complexity of biomolecules and the desire to achieve converged sampling, it is important that the QM method presents a good balance between accuracy and computational efficiency. Here, we report on the implementation of a QM/MM technique that combines a DFT approach specially designed for the study of complex systems using first-principles molecular dynamics simulations (FIREBALL) with the AMBER force fields and simulation programs .
We also present the application of this method, using DFT QM/MM molecular dynamics techniques, to study two different enzymatic reactions: phosphodiester bond cleavage by RNase A and DNA polymerization by HIV reverse transcriptase. In particular, the computational efficiency of our approach allowed the generation of free-energy surface maps to explore the large conformational space for the reactions, thus permitting a detailed analysis of alternative pathways.