The representation of the electrostatic interactions by Coulombic interactions between the atom-centered partial charges is a fundamental part of the molecular mechanics and empirical force field methods. The broad success of the AMBER force field family originates mainly in the RESP charge model (Bayly et al., 1993) that derives the partial charges to reproduce the electrostatic field around the molecules.

In this study we revisited the RESP charge derivation model in order to improve its description of the electrostatic potential around the molecules and thus the description of the electrostatic interactions in the force field. In particular, we re-optimized the atomic radii used for definition of the grid points for evaluation of the electrostatic field around the molecule. Some grid points introduced by the standard RESP procedure using Singh-Merz-Kollman radii (Singh et al., 1984) are deeply buried into the electron density, especially in case of aromatic molecules such as nucleobases, so that they significantly bias the fitted charges in an artificial way. In addition, we redefined the restraining scheme, in which we replaced the hyperbolic restraints toward zero charge values introduced by Bayly et al. by weighted parabolic restraints toward CM5 charges.(Marenich et al., 2012) These restraints are able to selectively eliminate the poor statistical of the ESP charges of the atoms buried in the molecule. On the other hand, they are negligibly small whenever the ESP charges are statistically well-defined. The redefined charges are able to reproduce the electrostatic potential around the molecules more accurately than standard RESP charges, especially for aromatic systems, and are able, e.g., to entirely eliminate underestimation of the base pairing interactions between nucleobases (Banas et al., 2012), which precludes accurate description of the nucleic acids by empirical force fields.

The authors gratefully acknowledge the support by the Ministry of Education, Youth and Sports of the Czech Republic and Czech Science Foundation no. 18-25349S and by the Operational Programme Research, Development and Education – European Regional Development Fund project no. CZ.02.1.01/0.0/0.0/16_019/0000754.

References

Bayly, C. I.; Cieplak, P.; Cornell, W. D.; Kollman, P. A. J. Phys. Chem. 1993, 97, 10269-10280.

Singh, U. C.; Kollman, P. A. J. Comput. Chem. 1984, 5, 129-145.