Probing the range of applicability of structure- and energy-adjusted QM/MM link bonds

The hydrogen-capping method is one of the most popular and widely used coupling-schemes for quantum mechanics/molecular mechanics (QM/MM)-molecular dynamics simulations of macromolecular systems. This is mostly due to the fact that it is fairly convenient to implement and parametrize, thus providing an excellent compromise between accuracy and computational effort. In this work, a viable and straight-forward approach to optimize the placing of the link atom on a suitable distance ratio between the frontier atoms is discussed. To further increase the accuracy, instead of global parameters for all amino acids, different parameter sets for each type of amino acid are derived. The dependency of the link bond parameters on the chemical environment and the used QM-method is probed to assess the range of applicability of the parametrization. Suitable sets of parameters for RI-MP2, B3LYP, (RI)-B3LYP-D3, and RI-BLYP-D3 at triple-zeta level for all relevant proteinogenic amino acids are presented. Furthermore, the scope and range of the perturbation, stemming from the introduction of link bonds is evaluated through application of the presented QM/MM scheme in calculations of the active site of 15S-lipoxygenase.