Upgraded AMBER Force Field for Zinc-Binding Residues and Ligands for Predicting Structural Properties and Binding Affinities in Zinc-Proteins

We developed a novel
force field in the context of AMBER parameterization
for glutamate and aspartate zinc­(II)-binding residues. The interaction
between the zinc ion and the coordinating atoms is represented by
a spherical nonbonded parameterization. The polarization effect due
to the zinc ion has been taken into account by redefining the atomic
charges on the residues through accurate quantum mechanical calculations.
The new zinc-binding ASP and GLU residues, along with the CYS and
HIS zinc-binding residues, parameterized in a recent work [Macchiagodena, M.; J. Chem. Inf. Model. 2019, 59, 3803−3816], allow
users to reliably simulate 96% of the Zn-proteins available in the
Protein Data Bank. The upgraded force field for zinc­(II)-bound residues
has been tested performing molecular dynamics simulations with an
explicit solvent and comparing the structural information with experimental
data for five different proteins binding zinc­(II) with GLU, ASP, HIS,
and CYS. We further validated our approach by evaluating the binding
free energy of (R)-2-benzyl-3-nitropropanoic acid
to carboxypeptidase A using a recently developed nonequilibrium alchemical
method. We demonstrated that in this setting it is crucial to take
into account polarization effects also on the metal-bound inhibitor.