Intermolecular forces, parameterization

Inter- and intramolecular forces (imf) are of vital importance in the quantitative description of structural effects on bioactivities and chemical properties. They can make a significant contribution to chemical reactivities and some physical properties as well. Types of intermolecular forces and their present parameterization are listed in Table 750. 

In the last two decades, substantial research occurred for the optimization of intermolecular force-field parameters [39-54]. In most cases, intermolecular parameters, especially Lennard-Jones parameters, cannot be strictly derived via physical considerations since they parameterize semiempirical models (i.e., based on classical mechanics) whom themselves only approximate reality. Hence, they are usually adjusted so that the resulting model is able to reproduce physical or chemical experimental target properties as accurately as possible. 

Cacelli, 1., Cimoli, A., Livotto, P.R., Prampolini, G. An automated approach for the parameterization of accurate intermolecular force-fields pyridine as a case smdy. J. Comp. Chem. 33, 1055-1067 (2012)... 

Electrostatic interactions can be most simply modeled as the Coulomb interaction between partial atomic charges, while the repulsion-dispersion part is usually described by a Lennard-Jones or, more accurately, an exp-6 form, each of which contains parameters that must be fixed. High-quality empirically fitted parameter sets have been developed, where the atom-atom interactions are parameterized to reproduce the structures, sublimation enthalpies and, sometimes, further observable properties of organic molecular crystals [73,74]. Their use has been very effective in CSP. Nonempirical approaches to fitting intermolecular force fields, where the parameters are derived from quantum mechanical calculations, have occasionally been applied for CSP [75-78], but these are currently limited to small molecules, so currently lack relevance for typical pharmaceutical molecules. 

The PM3-PIF models that have been developed in the past decade were aimed to enable more realistic studies of solutes in aqueous solutions. The fact that at the center of the model there is a correct structural and energetic description of the intermolecular forces governing the physical and chemical behavior of a condensed phase makes of these PM3-PIF models an excellent choice for a large exploration of the dynamic and structural properties of solutions. A clear obstacle for an ample use of these models is the need to obtain specific atomic pair parameters for each system and, as recently found, they are not necessarily transferable [34]. However, the advantage of having an inexpensive model including implicit polarizability and molecular flexibility with a satisfactory description of interactions makes worth the parameterization challenge. 

---