Rapid and Accurate Estimation of Quantum Average Electron Densities Using Newly-Defined Atom Types

A new computational tool, the Average Electron Density Estimator (AED-Est), has been developed along with a new scheme for assigning atom type, the AAA scheme. This combination of the AED-Est and the AAA scheme is designed to rapidly estimate properties, including electron populations, volumes, and average electron density (AED) values, with high precision and an accuracy comparable to values computed at the quantum levels. AED-Est gave comparable results when using three different sets/subsets of various neutral molecules. The AED-Est reference values were obtained using 553 molecules, and then tested on a separate set of 101 molecules. The <i>R</i> ² between the predicted values (obtained via the AED-Est tool) and the actual values (obtained via quantum simulations) reaches 0.99, and the RMSE values are at least 1 order of magnitude smaller than the average values. The new AAA scheme of defining atom types, which can be useful in designing new force fields, can significantly imporve the results compared to the general Amber force field, GAFF2, scheme. The AED-Est tool provided even better predictions of AED values for groups of atoms within a molecule, such as bioisosteric moieties, than for individual atoms. This has significant implications for fields such as drug discovery and the development of more effective therapeutics.