Directional Dependence of Hydrogen Bonds: A Density-Based Energy Decomposition Analysis and Its Implications on Force Field Development

Abstract

One well-known shortcoming of widely-used biomolecular force fields is the description of the directional dependence of hydrogen bonding (HB). Here we aim to better understand the origin of this difficulty and thus provide some guidance for further force field development. Our theoretical approaches center on a novel density-based energy decomposition analysis (DEDA) method [J. Chem. Phys., 131, 164112 (2009)], in which the frozen density energy is variationally determined through constrained search. This unique and most significant feature of DEDA enables us to find that the frozen density interaction term is the key factor in determining the HB orientation, while the sum of polarization and charge-transfer components shows very little HB directional dependence. This new insight suggests that the difficulty for current non-polarizable force fields to describe the HB directional dependence is not due to the lack of explicit polarization or charge-transfer terms. Using the DEDA results as reference, we further demonstrate that the main failure coming from the atomic point charge model can be overcome largely by introducing extra charge sites or higher order multipole moments. Among all the electrostatic models explored, the smeared charge distributed multipole model (up to quadrupole), which also takes account of charge penetration effects, gives the best agreement with the corresponding DEDA results. Meanwhile, our results indicate that the van der Waals interaction term needs to be further improved to better model directional hydrogen bonding.

Improved parameterization of interatomic potentials for rare gas dimers with density-based energy decomposition analysis

“…Taking advantage of this novel feature, we have systematically investigated the directional dependence of hydrogen bonding and our results clearly indicate that the frozen density interaction energy term is the key factor in determining the hydrogen bonding (HB) orientation, while the density relaxation energy term shows very little HB directional dependence. 57 This finding is very different from the current dominant view regarding the origin of hydrogen bonding directionality, and cannot be obtained with wave-function-based EDA approaches. On the other hand, these results indicate the importance of improving non-polarizable force fields by focusing on the frozen density interaction terms, and thus clearly demonstrate the novelty and power of the DEDA approach.…”

“…All electrostatic interactions for the smeared charge multipole model are calculated analytically as described in Ref. 57. With monopoles, dipoles, and quadrupoles directly calculated with the GDMA program [93][94][95] and quantum mechanical calculations, q i is obtained by the corresponding monopole subtracting Z i , and the width parameter of charge distribution a i is determined by minimizing the electrostatic potential difference between QM calculations and the smeared charge multipole model.…”

Minimal Basis Iterative Stockholder: Atoms in Molecules for Force-Field Development

“…The two remaining degrees of freedom can be used to model the penetration effect, 12,[22][23][24][25][26] i.e. the deviation of the electrostatic interactions from the simple point-charge model when the electronic densities begin to overlap.…”

GEM*: A Molecular Electronic Density-Based Force Field for Molecular Dynamics Simulations

“…40–49 The fitted densities are used to calculate each of the components of the QM intermolecular interaction (Coulomb, exchange–repulsion, polarization, charge–transfer, and dispersion). The use of continuous functions provides a more accurate description of molecular properties compared to conventional point charges.…”