Physical Chemistry

# Development and validation of AMBER-FB15-compatible force field parameters for phosphorylated amino acids

## Abstract

Phosphorylation of select amino acid residues is one of the most common tools for regulating protein structure and function. 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 blocked dipeptide forms of the phosphorylated amino acids serine, threonine, and tyrosine using the ForceBalance software package with the goal of improving agreement with experiment for these residues. Our optimized force field, denoted as FB18, is parameterized using high-quality \textit{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.

## Supplementary material

SI for FB18
List of parameter atom types for all residues/protonation states; description of the initial oxygen-phosphorous bond length parameter change for the dianionic residues; plots depicting the optimized parameter changes compared to the initial values; potential energy surface heat maps for all residues/protonation states.
FB18-AMBERFiles
AMBER input files for FB18