Chelator-Based Parameterization of the 12-6-4 Lennard-Jones Molecular Mechanics Potential for More Realistic Metal Ion-Protein Interactions.

Metal ions are associated with a variety of proteins and play critical roles in a wide range of biochemical processes. There are multiple ways to study and quantify protein-metal ion interactions, including molecular dynamics simulations. Recently, the AMBER molecular mechanics forcefield was modified to include a 12-6-4 Lennard-Jones potential, which allows for a better description of nonbonded terms through the additional pairwise C ij coefficients. Here, we demonstrate a method of generating C ij parameters that allows parametrization of specific metal ion-ligating groups in order to tune binding energies computed by thermodynamic integration. The new C ij coefficients were tested on a series of chelators: ethylenediaminetetraacetic acid, nitrilotriacetic acid, egtazic acid, and the EF1 loop peptides from the proteins lanmodulin and calmodulin. The new parameters show significant improvements in computed binding energies relative to existing force fields and produce coordination numbers and ion-oxygen distances that are in good agreement with experimental values. This parametrization method should be extensible to a range of other systems and could be readily adapted to tune properties other than binding energies.