The Monomer Electron Density Force Field (MEDFF): A Physically Inspired Model for Noncovalent Interactions

We
propose a methodology to derive pairwise-additive noncovalent
force fields from monomer electron densities without any empirical
input. Energy expressions are based on the symmetry-adapted perturbation
theory (SAPT) decomposition of interaction energies. This ensures
a physically motivated force field featuring an electrostatic, exchange-repulsion,
dispersion, and induction contribution, which contains two types of
parameters. First, each contribution depends on several fixed atomic
parameters, resulting from a partitioning of the monomer electron
density. Second, each of the last three contributions (exchange-repulsion,
dispersion, and induction) contains exactly one linear fitting parameter.
These three so-called interaction parameters in the model are initially
estimated separately using SAPT reference calculations for the S66x8
database of noncovalent dimers. In a second step, the three interaction
parameters are further refined simultaneously to reproduce CCSD­(T)/CBS
interaction energies for the same database. The limited number of
parameters that are fitted to dimer interaction energies (only three)
avoids ill-conditioned fits that plague conventional parameter optimizations.
For the exchange-repulsion and dispersion component, good results
are obtained for all dimers in the S66x8 database using one single
value for the associated interaction parameters. The values of those
parameters can be considered universal and can also
be used for dimers not present in the original database used for fitting.
For the induction component such an approach is only viable for the
dispersion-dominated dimers in the S66x8 database. For other dimers
(such as hydrogen-bonded complexes), we show that our methodology
remains applicable. However, the interaction parameter needs to be
determined on a case-specific basis. As an external validation, the
force field predicts interaction energies in good agreement with CCSD­(T)/CBS
values for dispersion-dominated dimers extracted from an HIV-II protease
crystal structure with a bound ligand (indinavir). Furthermore, experimental
second virial coefficients of small alkanes and alkenes are well reproduced.