Chelator-based parameterization of the 12-6-4LJ 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 by molecular dynamics simulations. Recently, the Amber molecular
mechanics forcefield was modified to include a 12-6-4LJ potential, which allows better description
of non-bonded terms through the additional pairwise Cij coefficients. Here, we demonstrate a
method of generating Cij parameters that allows parametrization of specific metal ion-ligating
groups in order to tune binding energies computed by thermodynamic integration. The new Cij
coefficients were tested on a series of chelators: EDTA, NTA, EGTA 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.