Abstract
Quantum mechanics/molecular mechanics (QM/MM) hybrid methods are currently the most powerful computational tools for studies of structure/function relations and catalytic sites embedded in macrobiomolecules (eg, proteins and nucleic acids). QM/MM methodologies are highly efficient since they implement quantum chemistry methods for modeling only the portion of the system involving bond-breaking/forming processes (QM layer), as influenced by the surrounding molecular environment described in terms of molecular mechanics force fields (MM layer). Some of the limitations of QM/MM methods when polarization effects are not explicitly considered include the approximate treatment of electrostatic interactions between QM and MM layers. Here, we review recent advances in the development of computational protocols that allow for rigorous modeling of electrostatic interactions in biomacromolecules and structural refinement, beyond the common limitations of QM/MM hybrid methods. We focus on photosystem II (PSII) with emphasis on the description of the oxygen-evolving complex (OEC) and its high-resolution extended X-ray absorption fine structure spectra (EXAFS) in conjunction with Monte Carlo structural refinement. Furthermore, we review QM/MM structural refinement studies of DNA G4 quadruplexes with embedded monovalent cations and direct comparisons to NMR data.