Recent advances in large-scale quantum chemistry development have enabled numerous ab initio calculations of large molecular and biomolecular systems, from the prediction of properties (protein structures, 1 protein-ligand binding affinities 2 ) to the investigation of dynamics. Density functional theory (DFT) is still the most widely employed method in large-scale quantum chemistry calculations for its balance of cost and accuracy in main group chemistry. Practical DFT calculations use density functional approximations (DFAs) for the exchange-correlation (xc) functional. However, most DFAs suffer from self-interaction errors, also called the delocalization error (DE). The DE affects the accuracy of DFT prediction of energetic properties (electron affinities, band gaps, 5 barrier heights, and dissociation energies ), density-derived properties (partial charges, molecular multipole moments), and geometry (bond lengths, bond angles). For large molecules like biological systems, the DE is also known to cause DFT self-consistent field (SCF) convergence issues due to the vanishing HOMO-LUMO gap. With a lot of computational resources wasted for each failed SCF, the convergence issue severely impacts the efficiency and usability of DFT in investigating biological systems.