Molecular Mechanics in Bioinorganic Chemistry

Abstract Molecular mechanics (MM) in bioinorganic chemistry separates into applications involving s‐block cations and those involving the d‐block elements. The former behave essentially as hard, charged spheres and can be treated efficiently and accurately with conventional force fields with little or no additional parameterization. The d‐block elements are significantly more challenging. The apparently complex electronic structures associated with the open d shell, the challenges of modeling reaction pathways within empirical methods, the lack of suitable software and MM parameters, and the rise of hybrid quantum mechanics/molecular mechanics (QM/MM) have all contributed to MM for transition metal systems being relatively underdeveloped. Given that metal‐ligand binding in coordination complexes and metalloenzyme active sites is essentially identical, this has significant consequences for bioinorganic applications. However, a critical handicap of any QM‐based method, including QM/MM, is that it is computationally expensive to carry out the configurational sampling or molecular dynamics necessary to get an accurate structure or reaction pathway. In contrast, MM is orders of magnitude faster and therefore has the potential to make a significant impact in bioinorganic chemistry. Encouraging progress is being made, especially with respect to d electron effects where ligand field molecular mechanics has demonstrated QM‐like performance at MM‐like speeds.