Rapid Calculation of Accurate Atomic Charges for Proteins via the Electronegativity Equalization Method

We
focused on the parametrization and evaluation of empirical models
for fast and accurate calculation of conformationally dependent atomic
charges in proteins. The models were based on the electronegativity
equalization method (EEM), and the parametrization procedure was tailored
to proteins. We used large protein fragments as reference structures
and fitted the EEM model parameters using atomic charges computed
by three population analyses (Mulliken, Natural, iterative Hirshfeld),
at the Hartree–Fock level with two basis sets (6-31G*, 6-31G**)
and in two environments (gas phase, implicit solvation). We parametrized
and successfully validated 24 EEM models. When tested on insulin and
ubiquitin, all models reproduced quantum mechanics level charges well
and were consistent with respect to population analysis and basis
set. Specifically, the models showed on average a correlation of 0.961,
RMSD 0.097 e, and average absolute error per atom 0.072 e. The EEM
models can be used with the freely available EEM implementation EEM_SOLVER.