A complete derivation of polarizable intermolecular potentials based on high-level, gas-phase quantum-mechanical calculations is proposed. The importance of appreciable accuracy together with inherent simplicity represents a significant endeavor when enhancement of existing force fields for biological systems is sought. Toward this end, symmetry-adapted perturbation theory (SAPT) can provide an expansion of the total interaction energy into physically meaningful e.g. electrostatic, induction and van der Waals terms. Each contribution can be readily compared with its counterpart in classical force fields. Since the complexity of the different intermolecular terms cannot be fully embraced using a minimalist description, it is necessary to resort to polyvalent expressions capable of encapsulating overlooked contributions from the quantum-mechanical expansion. This choice results in consistent force field components that reflect the underlying physical principles of the phenomena. This simplified potential energy function is detailed and definitive guidelines are drawn. As a proof of concept, the methodology is illustrated through a series of test cases that include the interaction of water and benzene with halide and metal ions. In each case considered, the total energy is reproduced accurately over a range of biologically relevant distances.
A strategy to infer solubilities from the combination of experiment and all-atom simulations is presented. From a single experimental estimate, the solubility of a substrate can be predicted in various environments from the related free energies of solvation. In the case of quercetin, the methodology was shown to reproduce the experimental solubilities in chloroform, water, acetonitrile, acetone, and tert-amyl alcohol within 0.5 log unit. The reliability of the estimates is markedly correlated to the accuracy of the experimental measure and to both the accuracy and precision of the computed free energies of solvation.
A strategy that incorporates in the macromolecular, non-polarizable CHARMM force field models of atomic charges and polarizabilities determined from high-level quantum mechanical calculations is probed in the paradigmatic case of metal ion complexes. Although the ab initio polarizable potential energy function is capable of hierarchizing correctly the affinity of a divalent calcium ion for three distinct electron-donor chelating agents, severe inaccuracies in the underlying contributions to the total binding energy, compared to a reference symmetry-adapted perturbation theory (SAPT) expansion, illuminate the incompleteness of the interaction model. The reported calculations suggest that mapping faithfully the signature electrostatic potential and induction energy of the isolated species is a necessary, albeit not sufficient condition to guarantee that intermolecular interactions be described accurately when key physical phenomena are evidently missing from a force field to which explicit induction effects have been introduced. They further suggest that in the present strategy, naive attempts to correct the flawed reproduction of the electrostatic and induction terms of the perturbative expansion-rooted, for instance, in an inappropriate representation of electron-cloud penetration-through de novo parametrization of the mathematically questionable "6-12" form of the van der Waals potential, common to many macromolecular force fields, are unavoidably bound to failure.
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