Revisiting Artifacts of Kohn-Sham Density Functionals for Biosimulation.

Abstract

We revisit the problem of unphysical charge density delocalization/fractionalization induced by the self-interaction error of common approximate Kohn-Sham (KS) density functional theory functionals on simulation of small to medium-sized proteins in a vacuum. Aside from producing unphysical electron densities and total energies, the vanishing of the HOMO-LUMO gap associated with the unphysical charge delocalization leads to an unphysical low-energy spectrum and catastrophic failure of most popular solvers for the KS self-consistent field (SCF) problem. We apply a robust quasi-Newton SCF solver [ Phys. Chem. Chem. Phys. 2024, 26, 6557] to obtain solutions for some of these difficult cases. The anatomy of the charge delocalization is revealed by the natural deformation orbitals obtained from the density matrix difference between the Hartree-Fock and KS solutions; the charge delocalization not only can occur between charged fragments (such as in zwitterionic polypeptides) but also involves neutral fragments. The vanishing-gap phenomenon and troublesome SCF convergence are both attributed to the unphysical KS Fock operator eigenspectra of molecular fragments (e.g., amino acids or their side chains). Analysis of amino acid pairs suggests that the unphysical charge delocalization can be partially ameliorated by the use of some range-separated hybrid functionals but not by semilocal or standard hybrid functionals. Last, we demonstrate that solutions without the unphysical charge delocalization can be located even for semilocal KS functionals highly prone to such defects, but such solutions have non-Aufbau character and are unstable with respect to mixing of the non-overlapping "frontier" orbitals. Caution should be exercised when unexpectedly small (or vanishing) HOMO-LUMO gaps and atypical SCF convergence patterns (e.g., oscillatory) are observed in KS DFT simulations in any context (bio or otherwise).