Electrostatic Point Charge Fitting as an Inverse Problem: Revealing the Underlying Ill-Conditioning

TL;DR

This paper analyzes the ill-conditioning in atom-centered point charge fitting for molecular electrostatics, revealing its intrinsic nature and proposing an analytical Lebedev grid model as a potential solution and alternative to multipole expansions.

Contribution

It introduces an analytical Lebedev grid model to understand and mitigate the ill-conditioning in point charge fitting, offering a new approach for electrostatic modeling.

Findings

Ill-conditioning arises from eigenvector curvature decay in the Hessian matrix.

Lebedev grid model reproduces multipole moments up to a certain rank.

Insights enable alleviation of ill-conditioning without external restraints.

Abstract

Atom-centered point charge model of the molecular electrostatics---a major workhorse of the atomistic biomolecular simulations---is usually parameterized by least-squares (LS) fitting of the point charge values to a reference electrostatic potential, a procedure that suffers from numerical instabilities due to the ill-conditioned nature of the LS problem. Here, to reveal the origins of this ill-conditioning, we start with a general treatment of the point charge fitting problem as an inverse problem, and construct an analytically soluble model with the point charges spherically arranged according to Lebedev quadrature naturally suited for the inverse electrostatic problem. This analytical model is contrasted to the atom-centered point-charge model that can be viewed as an irregular quadrature poorly suited for the problem. This analysis shows that the numerical problems of the point charge fitting are due to the decay of the curvatures corresponding to the eigenvectors of LS sum Hessian matrix. In part, this ill-conditioning is intrinsic to the problem and related to decreasing electrostatic contribution of the higher multipole moments, that are, in the case of Lebedev grid model, directly associated with the Hessian eigenvectors. For the atom-centered model, this association breaks down beyond the first few eigenvectors related to the high-curvature monopole and dipole terms; this leads to even wider spread-out of the Hessian curvature values. Using these insights, it is possible to alleviate the ill-conditioning of the LS point-charge fitting without introducing external restraints and/or constraints. Also, as the analytical Lebedev grid PC model proposed here can reproduce multipole moments up to a given rank, it may provide a promising alternative to including explicit multipole terms in a force field.