Chapter 3: QM/MM Simulations of Proteins: Is Explicit Inclusion of Polarization on the Horizon?¹

We review recent advances in protein simulations using combined quantum mechanics and classical mechanics (QM/MM) with emphasis on applications that focus on the polarization response in the MM region. Polarizable force-fields have recently been gaining momentum as standalone molecular mechanics (MM) applications, but their application to QM/MM simulations of proteins is only beginning to materialize. It is becoming increasingly crucial to account explicitly for polarizability in QM/MM simulations as many enzymatic sites represented at the QM level contain highly electrostatically active regions. The polarization response induced by highly-charged QM-regions in a QM/MM setup often extends far beyond the QM region. Thus, despite the serious challenges of incorporating polarizability in proteins, it has become the next necessary milestone for QM/MM, sometimes called QM/MMPOL. In this chapter, we discuss particular challenges in parametrization and current progress in the development of polarizable force-fields, the treatment of QM/MM boundaries, and free energy sampling, that arise from the implementation of polarizability. We illustrate the practical utility of the QM/MMPOL approach with multiple examples of free energy sampling and present two case studies involving proton transfer in the CIC transporter and carbonic anhydrase. Finally, we discuss possible approaches to tackle barriers to the incorporation of polarizability, including the expansion of machine learning-based approaches.