Abstract

Ionized groups carry net charge and thus play a major role in the electrostatic interactions between the ligand and receptor. However, their ionization states depend on such factors as the pH of the water phase, the interactions with other charges and with water molecules. Therefore, the ionization states must be predicted prior to the application of in silico screening or docking protocols. A typical virtual screening protocol searches for new heat compounds by testing hundreds of thousands or millions of small molecules against a particular target receptor. Differences in the size of receptors and the ligand, and the large number of small molecules to screen, require different computational approaches in predicting pKas of ionizable groups. On the receptor side, while the computational protocol does not have to be fast, it must account for shape of the receptor and the long range interactions of all ionizable groups within. Conversely, while the calculations of the ionization states of the ligand must be fast, they do not have to consider many long range interactions because of the small size of the ligand. These requirements resulted in the development of different protocols for computing pKas of the receptor and the ligand. The advantages and disadvantages of both are outlined in this paper. In addition, the formation of the receptor-ligand complex could dramatically change the electrostatic environment of the ionizable groups and cause proton uptake/release. Accounting for such phenomena can be critical for obtaining correct docking solutions.

Keywords: pKa's, receptor-ligand interactions, binding, proton uptake/release, protein-protein association