Performance of Protein–Ligand Force Fields for the Flavodoxin–Flavin Mononucleotide System

The ability to accurately perform molecular dynamics and free energy perturbation calculations for protein–ligand systems is of broad interest to the biophysical and pharmaceutical sciences. In this work, several popular force fields are evaluated for reproducing experimental properties of the flavodoxin/flavin mononucleotide system. Calculated 3J couplings from molecular dynamics simulations probing φ and χ1 dihedral angles are compared to over 1000 experimental measurements. Free energy perturbation calculations were also executed between different protein mutants for comparison with experimental data for relative free energies of binding. Newer versions of popular protein force fields reproduced 3J backbone and side chain couplings with good accuracy, with RMSD values near or below one hertz in most cases. OPLS-AA/M paired with CM5 charges for the ligand performed particularly well, both for the 3J couplings and FEP results, with a mean unsigned error for relative free energies of binding of 0.36 kcal/mol.