Upgrading and Validation of the AMBER Force Field
for Histidine and Cysteine Zinc(II)-Binding Residues in Sites with
Four Protein Ligands
Version 2 2019-08-21, 16:07
Version 1 2019-08-20, 19:20
Posted on 2019-08-21 - 16:07
We developed and
validated a novel force field in the context of
the AMBER parameterization for the simulation of zinc(II)-binding
proteins. The proposed force field assumes nonbonded spherical interactions
between the central zinc(II) and the coordinating residues. A crucial
innovative aspect of our approach is to account for the polarization
effects of the cation by redefining the atomic charges of the coordinating
residues and an adjustment of Lennard-Jones parameters of Zn-interacting
atoms to reproduce mean distance distributions. The optimal transferable
parametrization was obtained by performing accurate quantum mechanical
calculations on a training set of high-quality protein structures,
encompassing the most common folds of zinc(II) sites. The addressed
sites contain a zinc(II) ion tetra-coordinated by histidine and cysteine
residues and represent about 70% of all physiologically relevant zinc(II)
sites in the Protein Data Bank. Molecular dynamics simulations with
explicit solvent, carried out on several zinc(II)-binding proteins
not included in the training set, show that our model for zinc(II)
sites preserves the tetra-coordination of the metal site with remarkable
stability, yielding zinc(II)–X mean distances similar to experimental
data. Finally, the model was tested by evaluating the zinc(II)-binding
affinities, using the alchemical free energy perturbation approach.
The calculated dissociation constants correlate satisfactorily with
the experimental counterpart demonstrating the validity and transferability
of the proposed parameterization for zinc(II)-binding proteins.
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Macchiagodena, Marina; Pagliai, Marco; Andreini, Claudia; Rosato, Antonio; Procacci, Piero (2019). Upgrading and Validation of the AMBER Force Field
for Histidine and Cysteine Zinc(II)-Binding Residues in Sites with
Four Protein Ligands. ACS Publications. Collection. https://doi.org/10.1021/acs.jcim.9b00407
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AUTHORS (5)
MM
Marina Macchiagodena
MP
Marco Pagliai
CA
Claudia Andreini
AR
Antonio Rosato
PP
Piero Procacci
KEYWORDS
novel force fieldMolecular dynamics simulationsenergy perturbation approachdissociation constantsprotein structurespolarization effectsProtein Ligandsforce fieldAMBER parameterizationZn-interacting atomsAMBER Force Fielddistance distributionsLennard-Jones parameterscysteine residuesmetal siteProtein Data Bank