| Ionized groups carry net charge and thus play a major role in the electrostatic interactions between the ligand and receptor. Therefore understanding the role of electrostatics on protein-protein interactions is crucial for understanding the contribution of ionizable groups to the binding. However, their ionization states depend on many factors including pH of the water phase. The complexity comes from the fact that the pKa's of ionizable groups may be quite different from their standard values and even may change due to protein-protein binding. The main difficulty in modeling plausible ionization changes induced by the complex formation arises from the differences in the size of the receptors and the ligand, and the large number of small molecules to screen. The prediction of protonation states prior binding also requires different approaches: On the receptor side, while the computational protocol does not have to be fast, it must account for the 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.;In this thesis we are mainly interested in understanding the role of electrostatics on protein-protein interactions and how the ionizable residues give rise to measurable effects which can be quantified to understand binding and docking. The progress in predicting binding pockets is also investigated in this regard. We aim to understand perturbation of pKa's of ionizable groups during protein-protein interactions, because this phenomena results in pH-dependence of protein-protein binding free energy.;Protein-protein association is a pH-dependent process and thus the binding affinity depends on the local pH. In vitro the association occurs in particular cellular compartments, where the individual monomers are supposed to meet and form a complex. Since the monomers and the complex exist in the same micro environment, it is plausible that they coevolved toward its properties, in particular, toward the characteristic subcellular pH. Our results show that the pH-optimum of stability (the pH at which the monomers are most stable) of monomers is correlated with the pH-optimum of binding (the pH of maximal affinity) of the complexes made of the corresponding monomers. This confirms the observation (Biophysical Journal, 2006, 91(5), 1724-1736) which was delivered using the rigid body approach. Here we extend our previous study to include conformational changes induced by the binding on a set of 32 protein complexes and demonstrate that pH-optimum of binding can be roughly estimated using a parameter reflecting the net charge of individual monomers. |
