To describe binding of ligands to proteins, it is necessary to apply force field methods, either alone or in conjunction with a quantum mechanical core (QM/MM). Irrespective of the method used, the accuracy is strongly dependent on the force field used. An overview of several common force fields show that the quality varies substantially, even for simple model systems [Gundertofte et al., 1996].
When a ligand binds to a protein, the binding energy can roughly be divided into three parts: desolvation of the binding surfaces on protein and ligand, internal energy, and interaction energy. Some pitfalls in the calculation of the internal energy upon binding is illustrated by a recent study [Bostrøm et al., 1998]. It is shown that a comparison to the conformational ensemble in solution is critical to the results. A correct description of noncovalent interactions between the ligand and protein is also highly important in any model of binding. We have made a detailed study of one type of commonly encountered binding motif, the ammonium-carboxylate interaction. This type of bonding is commonly invoked, for example, in the salt bridges and in binding of neurotransmitters to receptors. However, in the gas phase, the bond cannot exist, but instead collapses to a neutral carboxylic acid-amine complex.
We have investigated the interaction type by high level quantum mechanical methods [Liljefors and Norrby, 1997] [Norrby and Liljefors, 1999]. The requirements for formation of the ion pair have been investigated by continuum solvation models together with small models for important environment moieties.