Are classical molecular mechanics calculations still useful in bioinorganic simulations?

There are currently no widely distributed molecular mechanics programs with inorganic force fields that allow the user to accurately model the structure of bioinorganic molecules without a prior parameterization of the metal coordination sphere. However, there are still times when the speed, accuracy and output of the calculations make inorganic molecular mechanics (MM) the method of choice. Bioinorganic molecular mechanical calculations are most commonly used to examine metalloproteins or parts of metalloproteins that are too large for analysis by QM/MM or DFT; to search large areas of conformational space; or in molecular dynamics. To illustrate the utility of inorganic molecular mechanics in bioinorganic chemistry, a brief review of simulations of bioinorganic compounds containing transitional metals published in the last 5 years is presented together with a computational analyses of methyl coenzyme-M reductase (MCR), which describes calculations that are too large for QM based methods, and urease, which is used as an example to illustrate how MM calculations can be used to sample large areas of conformational space. In the case of MCR, inorganic molecular mechanical conformational searches in conjunction with hole scans and normal-coordinate structural decomposition analysis are used to show how the protein matrix inhibits the non-planar deformations of the tetrapyrrole cofactor F430 and thereby changes its redox chemistry—an entatic effect. In our analysis of urease, inorganic molecular mechanical conformational searches were used to examine the conformational space available to the substrate and urea, and to examine potential mechanisms for its degradation.