Assessing the Performance of the Nonbonded Mg²⁺ Models in a Two-Metal-Dependent Ribonuclease

Magnesium ions (Mg²⁺), abundant in living cells, are essential for biomolecular structure, dynamics, and function. The biological importance of Mg²⁺ has motivated continuous development and improvement of various Mg²⁺ models for molecular dynamics (MD) simulations during the last decades. There are four types of nonbonded Mg²⁺ models: the point charge models based on a 12-6 or 12-6-4 type Lennard-Jones (LJ) potential, and the multisite models based on a 12-6 or 12-6-4 LJ potential. Here, we systematically assessed the performance of these four types of nonbonded Mg²⁺ models (21 models in total) in terms of maintaining a challenging intermediate state configuration captured in the structure of a prototypical two-metal-ion RNase H complex with an RNA/DNA hybrid. Our data demonstrate that the 12-6-4 multisite models, which account for charge-induced dipole interactions, perform the best in reproducing all the unique coordination modes in this intermediate state and maintaining the correct carboxylate denticity. Our benchmark work provides a useful guideline for MD simulations and structural refinement of Mg²⁺-containing biomolecular systems.