Combined quantum-mechanics/molecular-mechanics (QM/MM) approaches have become the method of choice for modeling reactions in biomolecular systems. Quantum-mechanical (QM) methods are required for describing chemical reactions and other electronic processes, such as charge transfer or electronic excitation. However, QM methods are restricted to systems of up to a few hundred atoms. However, the size and conformational complexity of biopolymers calls for methods capable of treating up to several 100,000 atoms and allowing for simulations over time scales of tens of nanoseconds. This is achieved by highly efficient, force-field-based molecular mechanics (MM) methods. Thus to model large biomolecules the logical approach is to combine the two techniques and to use a QM method for the chemically active region (e.g., substrates and co-factors in an enzymatic reaction) and an MM treatment for the surroundings (e.g., protein and solvent). The resulting schemes are commonly referred to as combined or hybrid QM/MM methods. They enable the modeling of reactive biomolecular systems at a reasonable computational effort while providing the necessary accuracy.

QM/MM Methods for Biomolecular Systems

https://pure.rug.nl/ws/files/3623614/2006JBiotechnolvBerkel.pdf

Flavoprotein monooxygenases, a diverse class of oxidative biocatalysts.

Flavin dependent monooxygenases.

We present a method to analyze biased molecular-dynamics and Monte Carlo simulations, also known as umbrella sampling. In the limiting case of a strong bias, this method is equivalent to thermodynamic integration. It employs only quantities with easily controllable equilibration and greatly reduces the statistical errors compared to the standard weighted histogram analysis method. We show the success of our approach for two examples, one analytic function, and one biological system.

/pdf/bridging-the-gap-between-thermodynamic-integration-and-424wslhoop.pdf

Bridging the gap between thermodynamic integration and umbrella sampling provides a novel analysis method: "Umbrella integration".

https://www.cell.com/cell-chemical-biology/pdf/S1074-5521(08)00040-9.pdf

Halogenation Strategies In Natural Product Biosynthesis

Para-hydroxybenzoate hydroxylase (EC 114132) is a flavoprotein involved in degradation of aromatic compounds, and it has become a model for enzymes involved in the oxygenation of a substrate The chemical and kinetic mechanisms of this enzyme are described and integrated with an outline of the structure of the protein from crystallographic analysis The structure is unusual because there is no recognizable domain for the binding of NADPH involved in the reaction Recently, mechanistic studies of site-directed mutants, combined with structural analyses, have provided some exciting discoveries about protein function The substrate during catalysis is largely isolated from solvent in the active site, a necessary condition for successful product formation The flavin ring structure moves substantially in the active site, probably to enable substrate and product exchange into this site and possibly to regulate the reduction of the flavin by NADPH A chain of H-bonds can connect p-hydroxy-benzoate in the act

W.J.H. van Berkel

Papers

Structure and mechanism of para-hydroxybenzoate hydroxylase.