Development and Validation of AMBER-FB15-Compatible Force Field Parameters for Phosphorylated Amino Acids

Phosphorylation
of select amino acid residues is one of the most
common biological mechanisms for regulating protein structures and
functions. While computational modeling can be used to explore the
detailed structural changes associated with phosphorylation, most
molecular mechanics force fields developed for the simulation of phosphoproteins
have been noted to be inconsistent with experimental data. In this
work, we parameterize force fields for the phosphorylated forms of
the amino acids serine, threonine, and tyrosine using the ForceBalance
software package with the goal of improving agreement with experiments
for these residues. Our optimized force field, denoted as FB18, is
parameterized using high-quality ab initio potential energy scans
and is designed to be fully compatible with the AMBER-FB15 protein
force field. When utilized in MD simulations together with the TIP3P-FB
water model, we find that FB18 consistently enhances the prediction
of experimental quantities such as 3J NMR
couplings and intramolecular hydrogen-bonding propensities in comparison
to previously published models. As was reported with AMBER-FB15, we
also see improved agreement with the reference QM calculations in
regions at and away from local minima. We thus believe that the FB18
parameter set provides a promising route for the further investigation
of the varied effects of protein phosphorylation.