Assessment of Empirical Models versus High-Accuracy Ab Initio Methods for Nucleobase Stacking: Evaluating the Importance of Charge Penetration

Abstract

Molecular mechanics (MM) force field models have been demonstrated to have difficulty reproducing certain potential energy surfaces of π-stacked complexes. Here, we examine the performance of the AMBER and CHARMM models relative to high-quality ab initio data across systematic helical parameter scans and typical B-DNA geometries for π-stacking energies of nucleobase dimers. These force fields perform best for typical B-DNA geometries (mean absolute error < 1 kcal mol(-1)), whereas errors typically approach ∼2 kcal mol(-1) for broader potential scans, with maximum errors > 10 kcal mol(-1) relative to high-quality ab initio reference interaction energies. The adequate performance of MM models near minimum energy structures is accomplished through cancellation of errors in various energy terms, whereas large errors at short intermolecular distances are caused by large MM electrostatics errors due to a lack of explicit terms modeling charge penetration effects.

General van der Waals potential for common organic molecules

“…SAPT2+), a previously published nucleobase stacking interaction energy database 21 with SAPT0 data was used in the validations. The QM energy decomposition was obtained using the SAPT0/jun-cc-pVDZ method.…”

“…With 28 pairs of vdW parameters for 9 chemical elements, we are able to reproduce vdW interaction energy for all dimers in this database with a RMSE of 1.68 kcal/mol (0.84 kcal/mol if within 90–110% of the equilibrium distances). Subsequently, the accuracy and transferability of the vdW2016 potential were validated by comparing to the SAPT0 energy of an additional set of stacked nucleobase 42 and newly generated cross-interacting dimers (S36x7). As a result, the vdW2016 potential yields strong correlations with R 2 of 0.983 for all base pairs and 0.994 for 259 heterodimers compared to the SAPT0 energy.…”

“…The problem with this approach however, is that the resulting vdW parameters are less transferable. 20 Given the recent advances in computational chemistry and the computing power, the noncovalent interaction energy components can be computed using highly accurate quantum mechanical methods 21 such as symmetry-adapted perturbation theory (SAPT). 22 Recently, we have developed a general electrostatic model to incorporate the charge penetration effect based on the atomic multipole moments in AMOEBA.…”

An optimized charge penetration model for use with the AMOEBA force field

“…Parker and Sherrill recently showed that without an explicit accounting for charge penetration, force fields struggle to accurately reproduce the ab initio electrostatic energies of these interactions. 8 For instance in an AC:GT base step, the mean absolute errors (MAE) of the AMBER 31, 32 and CHARMM 33 force fields relative to the SAPT electrostatic energy were over 20 kcal/mol. Likewise, we find that AMOEBA without charge penetration gives an electrostatic energy MAE over 20 kcal/mol as well.…”

“…Parker and Sherrill have recently shown that without charge penetration, it is difficult, if not impossible to accurately capture the electrostatics of interacting nucleobases. 8 These considerations show that if AMOEBA is to be successful in accurately modeling biologically relevant interactions such as nucleic acid folding or ligand binding, we must account for the short-range electrostatics of charge penetration.…”