Accelerating KSpot Charge Evaluation in Nucleic Acids via ABEEM Polarizable Force Field

Abstract

Accurate characterization of the complex electrostatic and polarization environments in nucleic acid–based systems is essential for reliable biomolecular simulations, where atomic charges play a central role. In this work, charges derived from the Kohn–Sham one-electron potential (KSpot), characterized by well-defined real-space topological boundaries, are incorporated into the atom-bond electronegativity equalization method (ABEEM) framework to balance quantum chemical accuracy and computational efficiency. Through systematic parametrization using fragment molecules representing diverse chemical environments, we developed a charge model for nucleic acid systems, termed KS–ABEEM. Validation results demonstrate that KS–ABEEM accurately reproduces KSpot real-space topological charges, yielding linear correlation coefficients of 0.9862 and 0.9885 for the training and test sets, respectively. The model also reliably predicts molecular dipole moments and electrostatically dominated intermolecular interaction energies, showing good agreement with quantum chemical calculations. Furthermore, KS–ABEEM avoids the high computational cost associated with conventional real-space topological integration methods. Compared with traditional topological approaches, the proposed KS–ABEEM achieves computational speedups of 102–104 while maintaining favorable computational scaling for large systems. Overall, this work provides an efficient route for extending quantum chemical topology-based charge models toward nucleic acid systems. Validation is presented for representative fragment molecules, hydrated clusters, and base-pair systems, while the computational efficiency and scalability of the approach for large all-atom nucleic acid structures are demonstrated through timing benchmarks, highlighting the potential of real-space topological descriptors for biomolecular simulations and polarizable force field development.